Nitrogen-containing compounds and pharmaceutical compositions thereof for the treatment of atrial fibrillation

ABSTRACT

The present invention provides a novel diazepine compound that blocks the I Kur  current or the Kv1.5 channel potently and more selectively than other K +  channels. The present invention relates to a diazepine compound represented by General Formula (1) 
     
       
         
         
             
             
         
       
         
         or a salt thereof, 
         wherein R 1 , R 2 , R 3 , and R 4  are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl; 
         R 2  and R 3  may be linked to form lower alkylene; 
         A 1  is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo; 
         Y 1  and Y 2  are each independently —N═ or —CH═; 
         and 
         R 5  is group represented by 
       
    
     
       
         
         
             
             
         
       
         
         wherein R 6  and R 7  are each independently hydrogen or organic group; 
         R 6  and R 7  may be linked to form a ring together with the neighboring group —X A —N—X B —; 
         X A  and X B  are each independently a bond, lower alkylene, etc.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application of U.S. application Ser. No. 13/388, 442, filed on Apr. 23, 2012, which is a National Stage of International Application No. PCT/JP2010/064545, filed on Aug. 20, 2010, which claims priorities from U.S. Patent Application Nos. 61/235,973 filed on Aug. 21, 2009, 61/235,981 filed on Aug. 21, 2009, 61/235,983 filed on Aug. 21, 2009 and 61/359,686 filed on Jun. 29, 2010, the contents of all of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to a nitrogen-containing compound and a pharmaceutical composition containing the same.

BACKGROUND ART

Atrial fibrillation (hereinafter referred to as “AF”) is the most frequently observed type of arrhythmia in clinical examinations. Although not a lethal arrhythmia, AF causes cardiogenic cerebral embolism, and is therefore recognized as an arrhythmia that greatly affects vital prognoses and QOL. It is known that the onset of AF increases with age, and that repeated AF strokes lead to chronic (serious) AF (The Journal of American Medical Association, 285, 2370-2375 (2001) and Circulation, 114, 119-123 (2006)).

To prevent chronic AF, which causes difficulty in restoring sinus rhythm and increases the risk of cardiogenic cerebral embolism, early defibrillation and subsequent prevention of recurrence (maintenance of the sinus rhythm) are required. Antiarrhythmic drugs (classes I and III) are most commonly used as pharmacotherapy, but these drugs achieve insufficient therapeutic effects, while causing serious side effects such as a proarrhythmic effect (Am. J. Cardiol., 72, B44-B49 (1993)).

The onset of AF is triggered by atrial premature contraction with underlining causes such as intra-atrial conduction delay, shortening and heterogeneity of the atrial refractory period (Nature Reviews DRUG DISCOVERY 4, 899-910 (2005)). It is known that the prolongation of refractory period of atrial muscle can terminate AF (defibrillation) or prevent the occurrence of AF. The action potential duration of the mammalian cardiac muscle is predominantly determined by voltage-dependent K⁺ channels. Inhibition of the K⁺ channel prolongs myocardial action potential duration, which results in prolongation of the refractory period (Nature Reviews DRUG DISCOVERY 5, 1034-49 (2006)). The action mechanism of class III antiarrhythmic drugs (e.g., Dofetilide) is to inhibit rapid delayed rectifier K⁺ current (I_(Kr)), K⁺ current encoded by HERG. However, since I_(Kr) is present in both the atria and ventricles, such drugs might cause ventricular arrhythmias, such as torsades de pointes (Trends Pharmacol. soc., 22, 240-246 (2001)).

Ultra-rapid delayed rectifier K⁺ current (I_(Kur)), K⁺ current encoded by Kv1.5, has been identified as K⁺ channel that is specifically expressed only in human atria (Cric. Res., 73, 1061-1076 (1993), J. Physiol., 491, 31-50 (1996) and Cric. Res., 80, 572-579 (1997)). Muscarine potassium current (I_(KACh)) encoded by two genes called GIRK1 and GIRK4 is known as a K⁺ channel specifically expressed inhuman atria (Nature 374, 135-141 (1995)). Accordingly, a pharmacologically acceptable substance that selectively blocks the I_(Kur) current (the Kv1.5 channel) or the I_(KACh) current (GIRK1/4 channel) can act selectively on the atrial muscle and is considered effective to exclude the proarrhythmic effect caused by prolonged action potential duration of the ventricular muscle.

SUMMARY OF INVENTION

The present specification discloses three inventions (three nitrogen-containing compounds each having a different structure). The inventions are respectively expressed as a “First Invention”, “Second Invention”, and “Third Invention”, which are described in detail below.

1. First Invention (Diazepine Compound)

The present inventors conducted extensive research to develop a compound that blocks the I_(Kur) current (Kv1.5 channel) and/or the I_(KACh) current (GIRK1/4 channel) potently and more selectively than other K⁺ channels. As a result, the inventors found that a novel diazepine compound represented by General Formula (1) below could be the desired compound. The present invention has been accomplished based on the above findings.

The present invention provides diazepine compounds, and pharmaceutical compositions comprising the diazepine compounds as summarized in items 1 to 16 below.

Item 1. A diazepine compound represented by General Formula (1)

or a salt thereof, wherein R¹, R², R³, and R⁴ are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl; R² and R³ may be linked to form lower alkylene; A¹ is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo; Y¹ and Y² are each independently —N═ or —CH═; R⁵ is group represented by

wherein R⁶ and R⁷ are each independently hydrogen or an organic group; R⁶ and R⁷ may be linked to form a ring together with the neighboring group —X_(A)—N—X_(B)—; X_(A) and X_(B) are each independently a bond, alkylene, alkenylene, —CO—, —SO₂—, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C(═S)—, —SO₂—, —CO—, —O—, —NH—, —CONH— and —SO₂NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in X_(A) and X_(B) is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl.

Item 2. A diazepine compound or a salt thereof according to Item 1, wherein R⁶ and R⁷ are each independently hydrogen, lower alkyl, cyclo lower alkyl, aryl or heterocyclic group, each of which is optionally substituted, and X_(A) and X_(B) are each independently a bond, lower alkylene, lower alkenylene, —CO—, —SO₂—, -lower alkylene-SO₂—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-lower alkylene-, -lower alkylene-SO₂—NH-lower alkylene-, —N(lower alkyl)-CO-lower alkylene-, —N(lower alkyl)-lower alkylene-CO—, —N(lower alkyl)-lower alkylene-N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—, —N(phenyl)-lower alkylene-CO—, —NH—CO—, —NH—CO-lower alkylene-, —NH-lower alkylene-, —O-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-CO—, —NH-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —S-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —SO₂—N(lower alkyl)-lower alkylene-, —SO₂—NH-lower alkylene-, -lower alkenylene-CO—N(lower alkyl)-lower alkylene-, lower alkylene-N(phenyl lower alkyl)-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—N(lower alkyl)-lower alkylene-, or —CO-lower alkylene-O—CO-lower alkylene-O—.

Item 3. A diazepine compound or a salt thereof according to Item 2, wherein R⁶ and R⁷ are each independently hydrogen, lower alkyl, cyclo lower alkyl, aryl or saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, each of which is optionally substituted.

Item 4. A diazepine compound or a salt thereof according to Item 3, wherein R⁶ and R⁷ are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, naphthyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl, thieno[2,3-b]pyrazinyl, 2,3-dihydroimidazo[2,1-b]thiazolyl, benzothiazolyl, indolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, benzothienyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furyl, benzofuryl, indazolyl, furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, benzo[1,3]dioxolyl, benzisoxazolyl, pyrazolo[2,3-a]pyridyl, indolizinyl, 2,3-dihydroindolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,4-dihydrocarbostyril, quinolyl, 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, pyrido[3,4-d]imidazolyl, pyrido[2,3-d]imidazolyl, chromanyl, 5,6,7,8-tetrahydroisoquinolyl, 3,4-dihydro-1H-isoquinolyl, 3,4-dihydroisoquinolyl, naphthyridinyl, 1,4-benzodioxanyl, cinnolinyl, quinoxalinyl, 2,3-dihydrobenz-1,4-oxazinyl, azetidinyl, 1,2,4-oxadiazolyl and azepanyl, each of which is optionally substituted.

Item 5. A diazepine compound or a salt thereof according to Item 4, wherein R⁶ and R⁷ are each independently selected from the group consisting of the following substituents (1) to (54):

(1) hydrogen; (2) lower alkyl; (3) cyclo lower alkyl optionally substituted with one or more phenyl lower alkoxys; (4) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1) to (4-27):

-   -   (4-1) cyano;     -   (4-2) hydroxyl;     -   (4-3) halogen;     -   (4-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogen,         hydroxyl, lower alkoxy, imidazolyl,         2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl;     -   (4-5) lower alkoxy optionally substituted with one or more         substituents selected from the group consisting of amino and         lower alkyl amino;     -   (4-6) pyridyl;     -   (4-7) thienyl;     -   (4-8) piperazinyl optionally substituted with one or more lower         alkyls;     -   (4-9) phenyl;     -   (4-10) pyrazolyl optionally substituted with one or more lower         alkyls;     -   (4-11) pyrimidinyl optionally substituted with one or more lower         alkyls;     -   (4-12) piperidyl optionally substituted with one or more lower         alkyls;     -   (4-13) furyl;     -   (4-14) carboxy;     -   (4-15) lower alkoxycarbonyl;     -   (4-16) amino optionally substituted with one or more         substituents selected from the group consisting of lower alkyl,         lower alkanoyl and lower alkylsulfonyl;     -   (4-17) lower alkylthio;     -   (4-18) triazolyl;     -   (4-19) imidazolyl;     -   (4-20) pyrrolidinyl optionally substituted with one or more         oxos;     -   (4-21) lower alkylsulfonyl;     -   (4-22) lower alkylenedioxy optionally substituted with one or         more halogens;     -   (4-23) nitro;     -   (4-24) oxazolyl;     -   (4-25) thiazolyl optionally substituted with one or more lower         alkyls;     -   (4-26) lower alkanoyl; and     -   (4-27) morpholinyl;         (5) naphthyl;         (6) furyl optionally substituted with one or more substituents         selected from the group consisting of lower alkyl optionally         substituted with halogen, carboxy, sulfo, pyridyloxy, lower         alkoxycarbonyl and phenyl;         (7) thienyl optionally substituted with one or more substituents         selected from the group consisting of lower alkyl, lower         alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower         alkoxycarbonyl, oxazolyl and furyl;         (8) imidazolyl optionally substituted with one or more         substituents selected from the group consisting of phenyl, lower         alkyl and halogen;         (9) pyrazolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         optionally substituted with halogen or lower alkoxy; cyclo lower         alkyl; halogen; phenyl optionally substituted with lower alkoxy;         furyl and thienyl;         (10) oxazolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         and phenyl;         (11) isoxazolyl optionally substituted with one or more         substituents selected from the group consisting of phenyl, lower         alkyl, thienyl and furyl;         (12) thiazolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         optionally substituted with halogen or lower alkoxy; phenyl;         phenoxy and lower alkanoylamino;         (13) pyrrolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         and lower alkoxycarbonyl;         (14) triazolyl optionally substituted with one or more lower         alkyls;         (15) pyridyl optionally substituted with one or more         substituents selected from the group consisting of the following         (15-1) to (15-14):     -   (15-1) halogen;     -   (15-2) cyano;     -   (15-3) amino optionally substituted with one or more         substituents selected from the group consisting of lower         alkanoyl and lower alkylsulfonyl;     -   (15-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogen,         lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower         alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl         optionally substituted with one or more hydroxyls;     -   (15-5) oxo;     -   (15-6) hydroxyl;     -   (15-7) lower alkoxy optionally substituted with one or more         phenyls;     -   (15-8) pyrrolidinyl;     -   (15-9) lower alkanoyl;     -   (15-10) morpholinyl;     -   (15-11) phenoxy;     -   (15-12) pyrazolyl;     -   (15-13) thienyl; and     -   (15-14) N-oxide         (16) pyrimidinyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         and phenyl;         (17) pyridazinyl;         (18) pyrazinyl optionally substituted with one or more phenyl         lower alkoxys;         (19) imidazo[2,1-b]thiazolyl optionally substituted with one or         more halogens;         (20) thieno[2,3-b]pyrazinyl;         (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted         with one or more phenyls;         (22) benzothiazolyl optionally substituted with one or more         lower alkyls;         (23) indolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl,         lower alkanoyl and halogen;         (24) imidazo[1,2-a]pyridyl or imidazo[1,5-a]pyridyl, each of         which is optionally substituted with one or more lower alkyls;         (25) benzothienyl optionally substituted with one or more lower         alkyls;         (26) benzimidazolyl optionally substituted with one or more         lower alkyls;         (27) 2,3-dihydrobenzo[b]furyl;         (28) benzofuryl optionally substituted with one or more         halogens;         (29) indazolyl optionally substituted with one or more lower         alkyls;         (30) furo[2,3-c]pyridyl or 6,7-dihydrofuro[2,3-c]pyridyl, each         of which is optionally substituted with one or more substituents         selected from the group consisting of oxo and lower alkyl         optionally substituted with lower alkoxy;         (31) furo[3,2-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each         of which is optionally substituted with one or more substituents         selected from the group consisting of oxo, lower alkyl         optionally substituted with halogen or lower alkoxy, halogen,         furyl, pyridyl and phenyl optionally substituted with one or         more substituents selected from the group consisting of amino         and lower alkoxy;         (32) thieno[2,3-c]pyridyl or 6,7-dihydrothieno[2,3-c]pyridyl,         each of which is optionally substituted with one or more         substituents selected from the group consisting of oxo group and         lower alkyl;         (33) thieno[3,2-c]pyridyl or 4,5-dihydrothieno[3,2-c]pyridyl,         each of which is optionally substituted with one or more         substituents selected from the group consisting of oxo and lower         alkyl;         (34) thieno[2,3-b]pyridyl;         (35) benzo[1,3]dioxolyl optionally substituted with one or more         halogens;         (36) benzisoxazolyl;         (37) pyrazolo[2,3-a]pyridyl;         (38) indolizinyl;         (39) 2,3-dihydroindolyl optionally substituted with one or more         substituents selected from the group consisting of oxo, lower         alkyl and lower alkanoyl;         (40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is         optionally substituted with one or more substituents selected         from the group consisting of lower alkyl, halogen and oxo;         (41) 1,2,3,4-tetrahydroisoquinolyl optionally substituted with         one or more oxos;         (42) quinolyl optionally substituted with one or more         substituents selected from the group consisting of amino         optionally substituted with one or two lower alkyls, lower         alkoxy, lower alkyl and oxo         (43) 1,2,3,4-tetrahydroquinolyl optionally substituted with one         or more substituents selected from the group consisting of lower         alkyl, pyridyl lower alkyl, aralkyl, lower alkoxy and oxo;         (44) 1,2-dihydroquinolyl optionally substituted with one or more         substituents selected from the group consisting of amino         optionally substituted with one or two lower alkyls, lower         alkoxy, lower alkyl and oxo;         (45) chromanyl optionally substituted with one or more lower         alkyls;         (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with         one or more oxos;         (47) 3,4-dihydroisoquinolyl optionally substituted with one or         more oxos;         (48) naphthyridinyl;         (49) 1,4-benzodioxanyl;         (50) cinnolinyl;         (51) quinoxalinyl;         (52) 2,3-dihydrobenz-1,4-oxazinyl optionally substituted with         one or more substituents selected from the group consisting of         lower alkyl and oxo;         (53) 2,3-dihydro-1H-benzo[d]imidazolyl optionally substituted         with one or more substituents selected from the group consisting         of lower alkyl and oxo; and         (54) piperidyl optionally substituted with one or more aryl         carbonyls.

Item 6. A diazepine compound or a salt thereof according to Item 5, wherein R⁶ and R⁷ are each independently (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30a), (30b), (31a), (31b), (32a), (32b), (33a), (33b), (35), (40a), (40b), (42a), (43a), (44a), and (53):

(1) hydrogen; (4a) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1), (4-2), (4-4), (4a-5), (4-10), (4a-16), (4-18), (4-19), (4-23), (4-26), and (4-27):

-   -   (4-1) cyano;     -   (4-2) hydroxyl;     -   (4-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogens,         hydroxyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, lower alkoxy,         imidazolyl, and morpholinyl;     -   (4a-5) lower alkoxy;     -   (4-10) pyrazolyl optionally substituted with one or more lower         alkyls;     -   (4a-16) amino optionally substituted with one or more lower         alkylsulfonyls;     -   (4-18) triazolyl;     -   (4-19) imidazolyl;     -   (4-23) nitro;     -   (4-26) lower alkanoyl; and     -   (4-27) morpholinyl;         (6a) furyl optionally substituted with one or more lower alkyls         optionally substituted with halogen;         (7a) thienyl optionally substituted with one or more lower         alkyls;         (8a) imidazolyl optionally substituted with one or more lower         alkyls;         (9a) pyrazolyl optionally substituted with one or more lower         alkyls optionally substituted with lower alkoxy;         (10a) oxazolyl optionally substituted with one or more lower         alkyls;         (11a) isoxazolyl optionally substituted with one or more lower         alkyls;         (12a) thiazolyl optionally substituted with one or more lower         alkyls optionally substituted with halogen;         (15a) pyridyl optionally substituted with one or more         substituents selected from the group consisting of the following         (15-1) to (15-5), (15a-7), (15-9), (15-11), (15-12) and (15-14):     -   (15-1) halogen;     -   (15-2) cyano;     -   (15-3) amino optionally substituted with one or more         substituents selected from the group consisting of lower         alkanoyl and lower alkylsulfonyl;     -   (15-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogen,         lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower         alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl         optionally substituted with one or more hydroxyls;     -   (15-5) oxo;     -   (15a-7) lower alkoxy;     -   (15-9) lower alkanoyl;     -   (15-11) phenoxy;     -   (15-12) pyrazolyl; and     -   (15-14) N-oxide         (16a) pyrimidinyl optionally substituted with one or more lower         alkyls;         (17) pyridazinyl         (18) pyrazinyl optionally substituted with one or more phenyl         lower alkoxys;         (23a) indolyl optionally substituted with one or more lower         alkyls;         (24a) imidazo[1,2-a]pyridyl;         (24b) imidazo[1,5-a]pyridyl optionally substituted with one or         more lower alkyls;         (26) benzimidazolyl optionally substituted with one or more         lower alkyls;         (29) indazolyl optionally substituted with one or more lower         alkyls;         (30a) furo[2,3-c]pyridyl optionally substituted with one or more         substituents selected from the group consisting of oxo and lower         alkyl;         (30b) 6,7-dihydrofuro[2,3-c]pyridyl optionally substituted with         one or more substituents selected from the group consisting of         oxo and lower alkyl;         (31a) furo[3,2-c]pyridyl optionally substituted with one or more         substituents selected from the group consisting of oxo and lower         alkyl;         (31b) 4,5-dihydrofuro[3,2-c]pyridyl optionally substituted with         one or more substituents selected from the group consisting of         oxo and lower alkyl optionally substituted with halogen or lower         alkoxy;         (32a) thieno[2,3-c]pyridyl optionally substituted with one or         more substituents selected from the group consisting of oxo and         lower alkyl;         (32b) 6,7-dihydrothieno[2,3-c]pyridyl optionally substituted         with one or more substituents selected from the group consisting         of oxo group and lower alkyl;         (33a) thieno[3,2-c]pyridyl optionally substituted with one or         more substituents selected from the group consisting of oxo and         lower alkyl;         (33b) 4,5-dihydrothieno[3,2-c]pyridyl optionally substituted         with one or more substituents selected from the group consisting         of oxo and lower alkyl;         (35a) benzo[1,3]dioxolyl;         (40a) isoquinolyl optionally substituted with one or more oxos;         (40b) 1,2-dihydroisoquinolyl optionally substituted with one or         more substituents selected from the group consisting of oxo and         lower alkyl;         (42a) quinolyl optionally substituted with one or more oxos;         (43a) 1,2,3,4-tetrahydroquinolyl optionally substituted with one         or more substituents selected from the group consisting of         aralkyl (e.g., phenyl lower alkyl, etc.), pyridyl lower alkyl         and oxo;         (44) 1,2-dihydroquinolyl optionally substituted with one or more         oxos; and         (53) 2,3-dihydrobenzo[d]imidazolyl optionally substituted with         one or more substituents selected from the group consisting of         lower alkyl and oxo.

Item 7. A diazepine compound or a salt thereof according to Item 6, wherein R⁶ and R⁷ are each independently phenyl, pyridyl, pyrazolyl, indolyl, 4,5-dihydrofuro[3,2-c]pyridyl, and 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or two substituents selected from the group consisting of oxo, lower alkyl, lower alkoxy lower alkyl, and lower alkylsulfonylamino.

Item 8. A diazepine compound or a salt thereof according to Item 7, which is selected from the group consisting of the following compounds:

-   1-ethyl-3,3,5-trimethyl-7-(3-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   1-ethyl-3,3,5-trimethyl-7-(2-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   1-ethyl-3,3,5-trimethyl-7-(2-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1,5-dihydro     benzo[b][1,4]diazepine-2,4-dione, -   1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-4-methyl-N-(2-pyridin-3-ylethyl)benzamide, -   N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzenesulfonamide, -   7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   N-(2-{[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)(2-pyridin-3-ylethyl)amino]methyl}-phenyl)methanesulfonamide, -   7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide.

Item 9. A diazepine compound according to Item 8, which is selected from the group consisting of the following compounds:

-   1-ethyl-3,3,5-trimethyl-7-(3-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione     dihydrochloride, -   1-ethyl-3,3,5-trimethyl-7-(2-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione     dihydrochloride, -   1-ethyl-3,3,5-trimethyl-7-(2-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione     dihydrochloride, -   1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino}ethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione     dihydrochloride, -   1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione     dihydrochloride, -   N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-4-methyl-N-(2-pyridin-3-ylethyl)benzamide     hydrochloride, -   N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzenesulfonamide, -   7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione     hydrochloride, -   N-(2-{[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)(2-pyridin-3-ylethyl)amino]methyl}phenyl)methanesulfonamide     dihydrochloride, -   7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione, -   1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione,     and -   N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide     hydrochloride.

Item 10. A diazepine compound or a salt thereof according to Item 1, wherein Y¹ and Y² are each —CH═.

Item 11. A pharmaceutical composition comprising a diazepine compound or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.

Item 12. A pharmaceutical composition according to Item 11 for preventing and/or treating arrhythmia.

Item 13. A diazepine compound or a salt thereof according to Item 1 for use in the pharmaceutical composition.

Item 14. Use of a diazepine compound or a salt thereof according to Item 1 as a pharmaceutical composition.

Item 15. Use of a diazepine compound or a salt thereof according to Item 1 for the production of a pharmaceutical composition.

Item 16. A method of preventing and/or treating arrhythmia, comprising administering to a patient a diazepine compound or a salt thereof according to Item 1.

The groups represented by, or substituents of, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A¹, X_(A), X_(B), Y¹ and Y² in the specification are described below.

The term “one or more” may be preferably 1 to 6, more preferably 1 to 3.

Examples of “lower alkyl” include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.

Examples of “alkylene” include linear or branched alkylene groups having 1 to 12 carbon atoms, such as the following “lower alkylene”, heptamethylene, octamethylene, decamethylene, and dodecamethylene.

Examples of “lower alkylene” include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene.

Examples of “alkenylene” include linear or branched alkenylene groups having 2 to 12 carbon atoms, such as the following “lower alkenylene”, heptenylene, octenylene, decenylene, and dodecenylene.

Examples of “lower alkenylene” include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as, ethenylene, propenylene, butenylene, pentenylene, and hexenylene.

Examples of “cyclo lower alkyl” include linear or branched cyclo alkyl having 3 to 8 carbon atoms, preferably 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclohexylmethyl.

Examples of “lower alkoxy” include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.

Examples of “halogen” are fluorine, chlorine, bromine, and iodine.

Examples of “lower alkylenedioxy” include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.

Examples of “lower alkanoyl” include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.

Examples of “lower alkoxycarbonyl” include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.

Examples of “aralkyl group” include lower alkyl group substituted with one or more aryl groups, such as benzyl and phenethyl.

Examples of “organic group” include lower alkyl, cyclo lower alkyl, aryl, and heterocyclic group, each of which is optionally substituted.

Examples of “aryl group” include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, and naphthyl.

Examples of “aroyl group” include benzoyl and naphthoyl.

Examples of “heterocyclic group” include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. Examples of preferable heterocyclic groups include the following (a) to (n):

(a) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, tetrahydropyridyl (e.g., 1,2,3,6-tetrahydropyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;

(b) saturated 3 to 8-membered, preferably 5 or 7-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azepanyl, 1,4-diazepanyl, etc.;

(c) saturated or unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 5 nitrogen atom(s), for example, decahydroquinolyl, indolyl, dihydroindolyl (e.g., 2,3-dihydroindolyl, etc.), isoindolyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazolyl, etc.), quinolyl, dihydroquinolyl (e.g. 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, etc.), tetrahydroquinolyl (1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, 1,2-dihydroisoquinolyl, etc.), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.), indazolyl, benzotriazolyl (e.g. benzo[d][1,2,3]triazolyl, etc.), tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-c]pyridyl, imidazo[1,5-a]pyridyl, etc.), naphthyridinyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolopyridyl (e.g., pyrazolo[2,3-a]pyridyl, etc.), tetrahydropyridoindolyl (e.g., 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, etc.), azabicyclooctanyl (e.g., (1R,5S)-8-azabicyclo[3.2.1]octanyl), etc.;

(d) saturated or unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s), for example, furyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl, etc.), tetrahydrofuryl, etc.;

(e) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 3 oxygen atom(s), for example, benzofuryl, dihydrobenzofuryl (e.g. 2,3-dihydrobenzo[b]furyl, etc.), chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl, etc.), benzodioxolyl (benzo[1,3]dioxolyl, etc.), etc.;

(f) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

(g) saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.;

(h) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzisoxazolyl, dihydrobenzoxazinyl (e.g., 2,3-dihydrobenz-1,4-oxazinyl, etc.), furopyridyl (e.g., furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, etc.), furopyrrolyl (e.g., furo[3,2-b]pyrrolyl etc.), etc.;

(i) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), isothiazolyl, etc.;

(j) saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;

(k) unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic groups containing a sulfur atom, for example, thienyl, etc.;

(l) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 3 sulfur atom(s), for example, benzothienyl (e.g. benzo[b]thienyl, etc.);

(m) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, thienopyridyl (e.g., thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, etc.), imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl, etc.), dihydroimidazothiazolyl (e.g., 2,3-dihydroimidazo[2,1-b]thiazolyl, etc.), thienopyrazinyl (e.g., thieno[2,3-b]pyrazinyl, etc.), etc.; and

(n) saturated or unsaturated 7- to 12-membered heterocyclic spiro groups containing 1 to 2 nitrogen atom(s), for example, azaspiroundecanyl (e.g., 3-azaspiro[5.5]undecanyl), etc.; and the like;

wherein said heterocyclic groups may be substituted with one or more suitable substituents.

Examples of more preferable heterocyclic groups include piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, triazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazo[2,1-b]thiazolyl, thieno[2,3-b]pyrazinyl, 2,3-dihydroimidazo[2,1-b]thiazolyl, benzothiazolyl, indolyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, benzothienyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furyl, benzofuryl, indazolyl, furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, benzo[1,3]dioxolyl, benzisoxazolyl, pyrazolo[2,3-a]pyridyl, indolizinyl, 2,3-dihydroindolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,4-dihydrocarbostyril, quinolyl, 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, pyrido[3,4-d]imidazolyl, pyrido[2,3-d]imidazolyl, chromanyl, 5,6,7,8-tetrahydroisoquinolyl, 3,4-dihydro-1H-isoquinolyl, 3,4-dihydroisoquinolyl, naphthyridinyl, 1,4-benzodioxanyl, cinnolinyl, quinoxalinyl, 2,3-dihydrobenz-1,4-oxazinyl, azetidinyl, 1,2,4-oxadiazolyl, and azepanyl, each of which is optionally substituted.

Substituents of “aryl group which is optionally substituted” represented by R⁶ and R⁷ are independently one or more substituents selected from the group consisting of:

(a1) cyano; (a2) hydroxyl; (a3) halogen; (a4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, lower alkoxy, imidazolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl; (a5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and lower alkyl amino; (a6) pyridyl; (a7) thienyl; (a8) piperazinyl optionally substituted with one or more lower alkyls; (a9) phenyl; (a10) pyrazolyl optionally substituted with one or more lower alkyls; (a11) pyrimidinyl optionally substituted with one or more lower alkyls; (a12) piperidyl optionally substituted with one or more lower alkyls; (a13) furyl; (a14) carboxy; (a15) lower alkoxycarbonyl; (a16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkanoyl and lower alkylsulfonyl; (a17) lower alkylthio; (a18) triazolyl; (a19) imidazolyl; (a20) pyrrolidinyl optionally substituted with one or more oxos; (a21) lower alkylsulfonyl; (a22) lower alkylenedioxy optionally substituted with one or more halogens; (a23) nitro; (a24) oxazolyl; (a25) thiazolyl optionally substituted with one or more lower alkyls; (a26) lower alkanoyl; (a27) sulfo; and (a28) morpholinyl.

Substituents of “heterocyclic group which is optionally substituted” represented by R⁶ and R⁷ are independently one or more substituents selected from the group consisting of:

(h1) oxo; (h2) lower alkyl optionally substituted with one or more substitutents selected from the group consisting of the following (h2-1) to (h2-10):

-   -   (h2-1) halogen;     -   (h2-2) hydroxyl;     -   (h2-3) amino optionally substituted with one or more         substituents selected from the group consisting of lower alkyl,         cyclo lower alkyl and lower alkanoyl;     -   (h2-4) pyridyl;     -   (h2-5) lower alkanoyloxy;     -   (h2-6) lower alkoxy;     -   (h2-7) aryloxy;     -   (h2-8) pyrimidinyl;     -   (h2-9) pyrrolidinyl optionally substituted with one or more         hydroxyls; and     -   (h2-10) imidazolyl optionally substituted with one or more lower         alkyls;         (h3) cyclo lower alkyl;         (h4) lower alkoxy optionally substituted with one or more         substitutents selected from the group consisting of pyridyl and         aryl;         (h5) aryl optionally substituted with one or more substituents         selected from the group consisting of lower alkyl optionally         substituted with one or more halogens; lower alkoxy; lower         alkanoyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl;         amino; lower alkyl amino, aryl and cyano;         (h6) aralkyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl,         lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower         alkoxycarbonyl, amino, lower alkyl amino, cyano and oxo;         (h7) heterocyclic group optionally substituted with one or more         substituents selected from the group consisting of lower alkyl,         lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower         alkoxycarbonyl, amino, lower alkyl amino, cyano and oxo;         (h8) hydroxyl;         (h9) halogen;         (h10) carboxy;         (h11) lower alkanoyl;         (h12) lower alkoxycarbonyl;         (h13) lower alkylenedioxy;         (h14) cyano;         (h15) nitro;         (h16) sulfo;         (h17) amino optionally substituted with one or more substituents         selected from the group consisting of lower alkyl, aryl, aroyl,         lower alkylsulfonyl and lower alkanoyl;         (h18) lower alkylthio;         (h19) lower alkylsulfonyl; and         (h20) aryloxy.

Preferable substituents represented by R⁶ and R⁷ are each independently selected from the group consisting of the following substituents (1) to (54):

(1) hydrogen; (2) lower alkyl; (3) cyclo lower alkyl optionally substituted with one or more phenyl lower alkoxys; (4) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1) to (4-27):

-   -   (4-1) cyano;     -   (4-2) hydroxyl;     -   (4-3) halogen;     -   (4-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogen,         hydroxyl, lower alkoxy, imidazolyl,         2-oxo-1,2,3,4-tetrahydroquinolyl and morpholinyl;     -   (4-5) lower alkoxy optionally substituted with one or more         substituents selected from the group consisting of amino and         lower alkyl amino;     -   (4-6) pyridyl;     -   (4-7) thienyl;     -   (4-8) piperazinyl optionally substituted with one or more lower         alkyls;     -   (4-9) phenyl;     -   (4-10) pyrazolyl optionally substituted with one or more lower         alkyls;     -   (4-11) pyrimidinyl optionally substituted with one or more lower         alkyls;     -   (4-12) piperidyl optionally substituted with one or more lower         alkyls;     -   (4-13) furyl;     -   (4-14) carboxy;     -   (4-15) lower alkoxycarbonyl;     -   (4-16) amino optionally substituted with one or more         substituents selected from the group consisting of lower alkyl,         lower alkanoyl and lower alkylsulfonyl;     -   (4-17) lower alkylthio;     -   (4-18) triazolyl;     -   (4-19) imidazolyl;     -   (4-20) pyrrolidinyl optionally substituted with one or more         oxos;     -   (4-21) lower alkylsulfonyl;     -   (4-22) lower alkylenedioxy optionally substituted with one or         more halogens;     -   (4-23) nitro;     -   (4-24) oxazolyl;     -   (4-25) thiazolyl optionally substituted with one or more lower         alkyls;     -   (4-26) lower alkanoyl; and     -   (4-27) morpholinyl;         (5) naphthyl;         (6) furyl optionally substituted with one or more substituents         selected from the group consisting of lower alkyl optionally         substituted with halogen, carboxy, sulfo, pyridyloxy, lower         alkoxycarbonyl and phenyl;         (7) thienyl optionally substituted with one or more substituents         selected from the group consisting of lower alkyl, lower         alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower         alkoxycarbonyl, oxazolyl and furyl;         (8) imidazolyl optionally substituted with one or more         substituents selected from the group consisting of phenyl, lower         alkyl and halogen;         (9) pyrazolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         optionally substituted with halogen or lower alkoxy; cyclo lower         alkyl; halogen; phenyl optionally substituted with lower alkoxy;         furyl and thienyl;         (10) oxazolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         and phenyl;         (11) isoxazolyl optionally substituted with one or more         substituents selected from the group consisting of phenyl, lower         alkyl, thienyl and furyl;         (12) thiazolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         optionally substituted with halogen or lower alkoxy; phenyl;         phenoxy and lower alkanoylamino;         (13) pyrrolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         and lower alkoxycarbonyl;         (14) triazolyl optionally substituted with one or more lower         alkyls;         (15) pyridyl optionally substituted with one or more         substituents selected from the group consisting of the following         (15-1) to (15-14):     -   (15-1) halogen;     -   (15-2) cyano;     -   (15-3) amino optionally substituted with one or more         substituents selected from the group consisting of lower         alkanoyl and lower alkylsulfonyl;     -   (15-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogen,         lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower         alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl         optionally substituted with one or more hydroxyls;     -   (15-5) oxo;     -   (15-6) hydroxyl;     -   (15-7) lower alkoxy optionally substituted with one or more         phenyls;     -   (15-8) pyrrolidinyl;     -   (15-9) lower alkanoyl;     -   (15-10) morpholinyl;     -   (15-11) phenoxy;     -   (15-12) pyrazolyl;     -   (15-13) thienyl; and     -   (15-14) N-oxide;         (16) pyrimidinyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl         and phenyl;         (17) pyridazinyl;         (18) pyrazinyl optionally substituted with one or more phenyl         lower alkoxys;         (19) imidazo[2,1-b]thiazolyl optionally substituted with one or         more halogens;         (20) thieno[2,3-b]pyrazinyl;         (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted         with one or more phenyls;         (22) benzothiazolyl optionally substituted with one or more         lower alkyls;         (23) indolyl optionally substituted with one or more         substituents selected from the group consisting of lower alkyl,         lower alkanoyl and halogen;         (24) imidazo[1,2-a]pyridyl or imidazo[1,5-a]pyridyl, each of         which is optionally substituted with one or more lower alkyls;         (25) benzothienyl optionally substituted with one or more lower         alkyls;         (26) benzimidazolyl optionally substituted with one or more         lower alkyls;         (27) 2,3-dihydrobenzo[b]furyl;         (28) benzofuryl optionally substituted with one or more         halogens;         (29) indazolyl optionally substituted with one or more lower         alkyls;         (30) furo[2,3-c]pyridyl or 6,7-dihydrofuro[2,3-c]pyridyl, each         of which is optionally substituted with one or more substituents         selected from the group consisting of oxo and lower alkyl         optionally substituted with lower alkoxy;         (31) furo[3,2-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each         of which is optionally substituted with one or more substituents         selected from the group consisting of oxo, lower alkyl         optionally substituted with halogen or lower alkoxy, halogen,         furyl, pyridyl and phenyl optionally substituted with one or         more substituents selected from the group consisting of amino         and lower alkoxy;         (32) thieno[2,3-c]pyridyl or 6,7-dihydrothieno[2,3-c]pyridyl,         each of which is optionally substituted with one or more         substituents selected from the group consisting of oxo group and         lower alkyl;         (33) thieno[3,2-c]pyridyl or 4,5-dihydrothieno[3,2-c]pyridyl,         each of which is optionally substituted with one or more         substituents selected from the group consisting of oxo and lower         alkyl;         (34) thieno[2,3-b]pyridyl;         (35) benzo[1,3]dioxolyl optionally substituted with one or more         halogens;         (36) benzisoxazolyl;         (37) pyrazolo[2,3-a]pyridyl;         (38) indolizinyl;         (39) 2,3-dihydroindolyl optionally substituted with one or more         substituents selected from the group consisting of oxo, lower         alkyl and lower alkanoyl;         (40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is         optionally substituted with one or more substituents selected         from the group consisting of lower alkyl, halogen and oxo;         (41) 1,2,3,4-tetrahydroisoquinolyl optionally substituted with         one or more oxos;         (42) quinolyl optionally substituted with one or more         substituents selected from the group consisting of amino         optionally substituted with one or two lower alkyls, lower         alkoxy, lower alkyl and oxo (43) 1,2,3,4-tetrahydroquinolyl         optionally substituted with one or more substituents selected         from the group consisting of lower alkyl, pyridyl lower alkyl,         aralkyl (e.g., phenyl lower alkyl), lower alkoxy and oxo;         (44) 1,2-dihydroquinolyl optionally substituted with one or more         substituents selected from the group consisting of amino         optionally substituted with one or two lower alkyls, lower         alkoxy, lower alkyl and oxo;         (45) chromanyl optionally substituted with one or more lower         alkyls;         (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with         one or more oxos;         (47) 3,4-dihydroisoquinolyl optionally substituted with one or         more oxos;         (48) naphthyridinyl;         (49) 1,4-benzodioxanyl;         (50) cinnolinyl;         (51) quinoxalinyl;         (52) 2,3-dihydrobenz-1,4-oxazinyl optionally substituted with         one or more substituents selected from the group consisting of         lower alkyl and oxo;         (53) 2,3-dihydro-1H-benzo[d]imidazolyl optionally substituted         with one or more substituents selected from the group consisting         of lower alkyl and oxo; and         (54) piperidyl optionally substituted with one or more aryl         carbonyls (e.g., phenyl carbonyl).

Examples of more preferable substituents represented by R⁶ and R⁷ include the following substituents (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30a), (30b), (31a), (31b), (32a), (32b), (33a), (33b), (35a), (40a), (40b), (42a), (43a), (44a), and (53):

(1) hydrogen; (4a) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1), (4-2), (4a-4), (4a-5), (4-10), (4a-16), (4-18), (4-19), (4-23), (4-26) and (4-27):

-   -   (4-1) cyano;     -   (4-2) hydroxyl;     -   (4a-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogen,         hydroxyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, lower alkoxy,         imidazolyl and morpholinyl;     -   (4a-5) lower alkoxy;     -   (4-10) pyrazolyl optionally substituted with one or more lower         alkyls;     -   (4a-16) amino optionally substituted with one or more lower         alkylsulfonyls;     -   (4-18) triazolyl     -   (4-19) imidazolyl;     -   (4-23) nitro;     -   (4-26) lower alkanoyl; and     -   (4-27) morpholinyl;         (6a) furyl optionally substituted with one or more lower alkyls         optionally substituted with halogen;         (7a) thienyl optionally substituted with one or more lower         alkyls;         (8a) imidazolyl optionally substituted with one or more lower         alkyls;         (9a) pyrazolyl optionally substituted with one or more lower         alkyls optionally substituted with lower alkoxy;         (10a) oxazolyl optionally substituted with one or more lower         alkyls;         (11a) isoxazolyl optionally substituted with one or more lower         alkyls;         (12a) thiazolyl optionally substituted with one or more lower         alkyls optionally substituted with halogen;         (15a) pyridyl optionally substituted with one or more         substituents selected from the group consisting of the following         (15-1) to (15-5), (15a-7), (15-9), (15-11), (15-12) and (15-14):     -   (15-1) halogen;     -   (15-2) cyano;     -   (15-3) amino optionally substituted with one or more         substituents selected from the group consisting of lower         alkanoyl and lower alkylsulfonyl;     -   (15-4) lower alkyl optionally substituted with one or more         substituents selected from the group consisting of halogen,         lower alkoxy, lower alkanoyloxy, cyclo lower alkyl amino, lower         alkyl amino, lower alkanoyl amino, hydroxyl and pyrrolidinyl         optionally substituted with one or more hydroxyls;     -   (15-5) oxo;     -   (15a-7) lower alkoxy;     -   (15-9) lower alkanoyl;     -   (15-11) phenoxy;     -   (15-12) pyrazolyl; and     -   (15-14) N-oxide;         (16a) pyrimidinyl optionally substituted with one or more lower         alkyls;         (17) pyridazinyl;         (18) pyrazinyl optionally substituted with one or more phenyl         lower alkoxys;         (23a) indolyl optionally substituted with one or more lower         alkyls;         (24a) imidazo[1,2-a]pyridyl;         (24b) imidazo[1,5-a]pyridyl optionally substituted with one or         more lower alkyls;         (26) benzimidazolyl optionally substituted with one or more         lower alkyls;         (29) indazolyl optionally substituted with one or more lower         alkyls;         (30a) furo[2,3-c]pyridyl optionally substituted with one or more         substituents selected from the group consisting of oxo and lower         alkyl;         (30b) 6,7-dihydrofuro[2,3-c]pyridyl optionally substituted with         one or more substituents selected from the group consisting of         oxo and lower alkyl;         (31a) furo[3,2-c]pyridyl optionally substituted with one or more         substituents selected from the group consisting of oxo and lower         alkyl;         (31b) 4,5-dihydrofuro[3,2-c]pyridyl optionally substituted with         one or more substituents selected from the group consisting of         oxo and lower alkyl optionally substituted with halogen or lower         alkoxy;         (32a) thieno[2,3-c]pyridyl optionally substituted with one or         more substituents selected from the group consisting of oxo and         lower alkyl;         (32b) 6,7-dihydrothieno[2,3-c]pyridyl optionally substituted         with one or more substituents selected from the group consisting         of oxo group and lower alkyl;         (33a) thieno[3,2-c]pyridyl optionally substituted with one or         more substituents selected from the group consisting of oxo and         lower alkyl;         (33b) 4,5-dihydrothieno[3,2-c]pyridyl optionally substituted         with one or more substituents selected from the group consisting         of oxo and lower alkyl;         (35a) benzo[1,3]dioxolyl;         (40a) isoquinolyl optionally substituted with one or more oxos;         (40b) 1,2-dihydroisoquinolyl optionally substituted with one or         more substituents selected from the group consisting of oxo and         lower alkyl;         (42a) quinolyl optionally substituted with one or more oxos;         (43a) 1,2,3,4-tetrahydroquinolyl optionally substituted with one         or more substituents selected from the group consisting of         aralkyl (e.g., phenyl lower alkyl), pyridyl lower alkyl and oxo;         (44a) 1,2-dihydroquinolyl optionally substituted with one or         more oxos; and         (53) 2,3-dihydrobenzo[d]imidazolyl optionally substituted with         one or more substituents selected from the group consisting of         lower alkyl and oxo.

Preferred embodiments of the diazepine compound of Formula (1) are described below.

R¹, R², R³ and R⁴ are each independently hydrogen, lower alkyl, cyclo lower alkyl or lower alkoxy lower alkyl, and preferably hydrogen, C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl), C₁₋₆ cyclo alkyl (e.g., cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl), or C₁₋₆ alkoxy C₁₋₆ alkyl (e.g., 2-methoxyethyl and 2-ethoxyethyl).

Both Y¹ and Y² are —C═.

A¹ is lower alkylene, and preferably C₁₋₆ alkylene such as methylene, ethylene, trimethylene, or tetramethylene. X_(A) and X_(B) are each independently lower alkylene, which is preferably C₁₋₆ alkylene such as methylene, ethylene, trimethylene, or tetramethylene; a bond; —CO—; or —SO₂—.

R⁶ and R⁷ are each independently a group selected from (1), (4a), (6a), (7a), (8a), (9a), (10a), (11a), (12a), (15a), (16a), (17), (18), (23a), (24a), (24b), (26), (29), (30b), (31b), (32b), (33b), (35a), (40b), (42a), (43a), (44a), and (53):

Examples of X_(A) and X_(B) include a bond, lower alkylene, lower alkenylene, —CO—, —SO₂—, -lower alkylene-SO₂—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-lower alkylene-, -lower alkylene-SO₂—NH-lower alkylene-, —N(lower alkyl)-CO-lower alkylene-, —N(lower alkyl)-lower alkylene-CO—, —N(lower alkyl)-lower alkylene-N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—, —N(phenyl)-lower alkylene-CO—, —NH—CO—, —NH—CO-lower alkylene-, —NH-lower alkylene-, —O-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-CO—, —NH-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —S-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —SO₂—N(lower alkyl)-lower alkylene-, —SO₂—NH-lower alkylene-, -lower alkenylene-CO—N(lower alkyl)-lower alkylene-, lower alkylene-N(phenyl lower alkyl)-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—N(lower alkyl)-lower alkylene-, and —CO-lower alkylene-O—CO-lower alkylene-O—.

Preferred examples of X_(A) and X_(B) include a bond, lower alkylene, lower alkenylene, —CO—, —SO₂—, -lower alkylene-SO₂—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, and —O-lower alkylene-.

Either of the two bonds in X_(A) may be bonded to R¹ or N, and either of the two bonds in X_(B) may be bonded to R² or N.

The ring formed when R⁶ and R⁷ are linked together with the neighboring group —X_(A)—N—X_(B)— is a nitrogen-containing heterocyclic group optionally having one or more substituents. Examples of the nitrogen-containing heterocyclic group include the above-mentioned heterocyclic groups (a) to (c), (f) to (j), and (m) to (n). Examples of substituents of the nitrogen-containing heterocyclic group optionally having one or more substituents include the above-mentioned substituents (h1) to (h20).

The diazepine compound of the present invention represented by Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification. For example, the diazepine compound or its salt can be produced according to the processes shown in the following reaction formulae.

wherein R¹, R², R³, R⁴, R⁵, A¹, Y¹ and Y² are the same as above, and X¹ is a leaving group.

The reaction of the compound of Formula (2) with the compound of Formula (3) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound and/or catalyst.

Examples of the leaving groups represented by X¹ include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkane sulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C₁₋₆) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.

A wide variety of known basic compounds can be used as the basic compound. Examples of such basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.

Examples of the catalyst include palladium compounds such as palladium acetate, bis(tributyltin)/bis(dibenzylideneacetone) palladium, copper iodide/2,2′-bipyridyl, bis(dibenzylideneacetone) palladium, copper iodide/bis(triphenylphosphine) palladium dichloride, tris(dibenzylideneacetone) dipalladium, R-tris (dibenzylideneacetone)-dipalladium, S-tris (dibenzylideneacetone) dipalladium, palladium(II) acetate, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), and tetrakis (triphenylphosphine) palladium.

Additives (ligands etc.) can be used together with the catalyst. Examples of the additive include compounds such as R-2,2′-bis diphenylphosphino)-1,1′-binaphthyl (R-BINAP), S-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), RAC-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (RAC-BINAP), and 2,2-bis(diphenylimidazolidinyliden), xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and borates such as tri-tert-butylphosphine tetrafluoroborate, and a mixture thereof.

The above reaction may be performed by adding to the reaction system, as required, an alkali metal iodide serving as a reaction accelerator, such as potassium iodide or sodium iodide.

The compound of Formula (3) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (2).

The amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (2).

The catalyst is appropriately used in a typical catalytic amount, preferably 0.0001 to 1 moles, and more preferably 0.001 to 0.5 moles, per mole of the compound (2).

The reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.

wherein R¹, R², R³, R⁴, Y¹ and Y² are the same as above.

The reaction converting the compound of Formula (4) to the compound of Formula (1a) can be performed by catalytic reduction of the compound of Formula (4) in a suitable solvent, in the presence of a catalytic hydrogenation reducing agent.

The solvent is not limited as long as it does not adversely affect the reduction reaction. Examples of such solvents include carboxylic acids such as formic acid and acetic acid; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; and lower (e.g., C₁₋₆) alcohols such as methanol, ethanol, and isopropanol.

Examples of catalytic hydrogenation reducing agents include palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.

The amount of catalytic hydrogenation reducing agent is typically 0.1 to 40 wt %, and preferably 1 to 20 wt %, based on the compound of Formula (4).

The reaction can be typically performed in a hydrogen atmosphere at atmospheric pressure to about 20 atm, and preferably atmospheric pressure to 10 atm; or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate. The reaction temperature may typically be about −30 to about 100° C., and preferably about 0 to about 60° C.

wherein R¹, R², R³, R⁴, Y¹ and Y² are the same as above; and R⁸ is lower alkyl.

The reaction converting the compound of Formula (5) to the compound of Formula (6) can be performed in a general inert solvent or without using any solvent, in the presence of an azide compound, a basic compound, and a lower (C₁₋₆) alcohol (R⁸OH).

Examples of “lower alkyl” represented by R⁸ include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and tert-butyl, with tert-butyl being preferred.

Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.

Examples of azide compounds include sodium azide, lithium azide, and diphenylphosphoryl azide (DPPA).

Examples of usable basic compounds include organic bases such as triethylamine; tripropylamine; diisopropylethylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO).

The reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.

In the reaction, a carboxylic azide is produced from the carboxylic compound of Formula (5) and an azide compound, and the carboxylic azide undergoes subsequent Curtius rearrangement to produce an isocyanate. The isocyanate reacts with a lower (C₁₋₆) alcohol (R⁸OH) to produce a urethane compound of Formula (6).

Next, the reaction converting the compound of Formula (6) to the compound of Formula (1b) can be performed by solvolysis in a suitable solvent, in the presence of an acid or basic compound.

Examples of usable solvents include water; lower (C₁₋₆) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, and mixtures thereof.

Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, thioglycolic acid, trifluoroacetic acid, and sulfonic acids such as p-toluenesulfonic acid. These acids may be used singly or in a combination of two or more.

Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds can be used singly or in a combination of two or more.

The amount of acid or basic compound is typically at least 1 mole, and preferably about 1 to about 10 moles, per mole of the compound of Formula (6).

The solvolysis reaction (particularly the hydrolysis) advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 10 minutes to about 80 hours.

Particularly when R⁸ is tert-butyl, the solvolysis can be easily accomplished using the above-mentioned acids (particularly hydrochloric acid and the like) to produce the compound of Formula (1b).

Alternatively, the compound of Formula (5) can be directly converted to the compound of Formula (1b). This reaction can be performed by reacting the compound (5) with an azide compound in a general inert solvent or without using any solvent, in the presence of a basic compound, followed by treating the product with water. In this reaction, an isocyanate is produced from the above-mentioned carboxylic compound of Formula (5) and azide compound, and the isocyanate is hydrolyzed to produce the amine compound of Formula (1b).

wherein R¹, R², R³, R⁴, Y¹ and Y² are the same as above; and A^(1a) is lower alkylene with 3 or more carbon atoms.

Examples of “lower alkylene with 3 or more carbon atoms” represented by A^(1a) include alkylene groups with 3 to 6 carbon atoms, such as trimethylene, tetramethylene, pentamethylene, and hexamethylene.

The reaction converting the compound of Formula (7) to the compound of Formula (1c) can be performed by reacting the compound (7) with hydrazine in a suitable solvent, or by hydrolysis. Here, hydrazine hydrate may be used as the hydrazine.

Examples of solvents used in reacting the hydrazine include water; halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate and ethyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; acetonitrile; pyridine; and mixtures thereof.

The amount of hydrazine is typically at least about 1 mole, and preferably about 1 to about 5 moles, per mole of the compound of Formula (7).

The reaction is performed typically at about 0 to about 120° C., and preferably at about 0 to about 100° C., and is typically completed in about 0.5 to about 5 hours.

wherein R¹, R², R³, R⁴, R⁶, R⁷, X_(A), A¹, Y¹ and Y² are the same as above; and R^(7a) is hydrogen or lower alkyl. Examples of “lower alkyl” represented by R^(7a) include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.

The reaction between the compound of Formula (1d) and the compound of Formula (8) is performed, for example, in a suitable solvent or without using any solvent, in the presence of a reducing agent.

Examples of usable solvents include water; lower (C₁₋₆) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as formic acid, and acetic acid; ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme, and diglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; acetonitrile; and mixtures thereof.

Examples of reducing agents include aliphatic acids such as formic acid; aliphatic acid alkali metal salts such as sodium formate; hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, lithium aluminium hydride, and mixtures thereof, or mixtures of aliphatic acids or aliphatic acid alkali metal salts with hydride reducing agents; and catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.

When an aliphatic acid such as formic acid, or an aliphatic acid alkali metal salt such as sodium formate is used as a reducing agent, a suitable reaction temperature is typically about room temperature to about 200° C., and preferably about 50 to about 150° C. The reaction is typically completed in about 10 minutes to about 10 hours. Preferably, the aliphatic acid or aliphatic acid alkali metal salt is used in large excess relative to the compound of Formula (1d).

When a hydride reducing agent is used, a suitable reaction temperature is typically about −80 to about 100° C., and preferably about −80 to about 70° C. The reaction is typically completed in about 30 minutes to about 60 hours. The hydride reducing agent is typically used in an amount of about 1 to about 20 moles, and preferably about 1 to about 10 moles, per mole of the compound of Formula (1d). Particularly when lithium aluminium hydride is used as a hydride reducing agent, it is preferable to use as a solvent an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, or diglyme; or an aromatic hydrocarbon such as benzene, toluene, or xylene. To the reaction system may be added an amine such as trimethylamine, triethylamine, or N-ethyldiisopropylamine; or a molecular sieve such as molecular sieve 3A (MS-3A) or molecular sieve 4A (MS-4A).

When a catalytic hydrogenation reducing agent is used, the reaction is typically performed at about −30 to about 100° C., and preferably at about 0 to about 60° C., in a hydrogen atmosphere at typically about atmospheric pressure to about 20 atm, and preferably at about atmospheric pressure to about 10 atm, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate. The reaction is typically completed in about 1 to about 12 hours. The catalytic hydrogenation reducing agent is typically used in an amount of about 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, based on the compound of Formula (1d).

In the reaction of the compound of Formula (1d) and the compound of Formula (8), the compound of Formula (8) is typically used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the compound of Formula (1d).

The compound of Formula (8) may also be a hydrated compound wherein a water molecule is attached to a carbonyl group.

wherein R¹, R², R³, R⁴, R⁶, R⁷, X_(A), X_(B), A¹, X^(B), Y¹ and Y² are the same as above.

The reaction of the compound of Formula (1d) with the compound of Formula (9) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.

Alternatively, the reaction of the compound of Formula (1d) with the compound of Formula (9) can be performed by the known “Ullmann condensation” etc. The reaction can be preferably adopted especially when X_(B) is a bond and R⁷ is aryl or heterocyclic (especially unsaturated heterocyclic) group optionally substituted. For example, the reaction can be carried out in a solvent (e.g., toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO)), in the presence of copper compound (e.g., copper oxides, copper halides such as copper iodide), a basic compound (e.g., sodium tert-butoxide, K3PO4 and Cs2CO3), and if necessary a phosphine (e.g., triphenylphosphine, xantphos, tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), tetrafluoroborate, N,N′-dimethylethylenediamine, and L-proline).

The reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.

wherein R¹, R², R³, R⁴, R⁵, Y¹ and Y² are the same as above.

The reaction of the compound of Formula (10) with the compound of Formula (3) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1d) with the compound of Formula (8) shown in Reaction Formula 5 above.

wherein R², R³, R⁴, R⁵, A¹, X¹, Y¹ and Y² are the same as above; and R^(1a) is lower alkyl.

Examples of “lower alkyl” represented by R^(1a) include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.

The reaction of the compound of Formula (1 g) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.

In this reaction, when R⁴ is hydrogen in the compound of Formula (1 g), a compound may be obtained wherein the 1- and 5-positions of the benzodiazepine skeleton are simultaneously replaced by the group R^(1a).

wherein R^(1a), R⁴, R⁵, A¹, X¹, Y¹ and Y² are the same as above.

The reaction of the compound of Formula (1i) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.

In this reaction, when R⁴ is hydrogen in the compound of Formula (1i), a compound may be obtained wherein the 1-, 3-, and 5-positions of the benzodiazepine skeleton are simultaneously replaced by the group R^(1a).

wherein R¹, R⁴, R⁵, A¹, X¹, Y¹ and Y² are the same as above; and R^(2a) is lower alkyl.

Examples of “lower alkyl” represented by R^(2a) include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.

The reaction of the compound of Formula (1k) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.

In this reaction, when R¹ and/or R⁴ is hydrogen in the compound of Formula (1k), a compound may be obtained wherein the 1-, 3-, and 5-positions of the benzodiazepine skeleton are simultaneously replaced by the group R^(2a).

wherein R², R³, R⁴, R^(1a), X¹, Y¹ and Y² are the same as above; R⁹ is lower alkoxy; and R¹⁰ is lower alkoxycarbonyl.

Examples of “lower alkoxy” represented by R⁹ include linear or branched alkoxy groups with 1 to 6 carbon atoms, such as methoxy, and ethoxy. Examples of “lower alkoxycarbonyl” represented by R¹⁰ include (C₁₋₆ alkoxy) carbonyl groups, such as methoxycarbonyl, ethoxycarbonyl.

In the reaction of the compound of Formula (13) with the compound of Formula (14), the compound of Formula (13) is reacted with the carboxylic acid compound of Formula (14) through a general amide bond formation reaction. Conditions for known amide bond formation reactions can be easily employed in this amide formation reaction. For example, the following reaction methods can be employed: (i) a mixed acid anhydride method, in which Carboxylic Acid (14) is reacted with an alkyl halocarboxylate to form a mixed acid anhydride, which is then reacted with Amine (13); (ii) an active ester method, in which Carboxylic Acid (14) is converted to an activated ester such as a phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, or 1-hydroxybenzotriazole ester, or to an activated amide with benzoxazoline-2-thione, and the activated ester or amide is reacted with Amine (13); (iii) a carbodiimide method, in which Carboxylic Acid (14) is subjected to a condensation reaction with Amine (13) in the presence of an activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), or carbonyldiimidazole; and (iv) other methods, for example, a method in which Carboxylic Acid (14) is converted to a carboxylic anhydride using a dehydrating agent such as acetic anhydride, and the carboxylic anhydride is reacted with Amine (13), a method in which an ester of Carboxylic Acid (14) with a lower (C₁₋₆) alcohol is reacted with Amine (13) at a high pressure and a high temperature, and a method in which an acid halide of Carboxylic Acid (14), i.e., a carboxylic acid halide, is reacted with Amine (13).

Generally, the mixed acid anhydride method (i) is performed in a solvent, in the presence or absence of a basic compound. Any solvents used for conventional mixed acid anhydride methods are usable. Specific examples of usable solvents include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures thereof.

Examples of usable basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic bases, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; potassium hydride; sodium hydride; potassium; sodium; sodium amide; and metal alcoholates such as sodium methylate and sodium ethylate.

Examples of alkyl halocarboxylates usable in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. In this method, Carboxylic Acid (14), an alkyl halocarboxylate, and Amine (13) are preferably used in equimolar amounts, but each of the alkyl halocarboxylate and Carboxylic Acid (14) can also be used in an amount of about 1 to about 1.5 moles per mole of Amine (13).

The reaction is typically performed at about −20 to about 150° C., and preferably at about 10 to about 50° C., typically for about 5 minutes to about 30 hours, and preferably for about 5 minutes to about 25 hours.

Method (iii), in which a condensation reaction is performed in the presence of an activating agent, can be performed in a suitable solvent in the presence or absence of a basic compound. Solvents and basic compounds usable in this method include those mentioned hereinafter as solvents and basic compounds usable in the method in which a carboxylic acid halide is reacted with Amine (13) mentioned above as one of the other methods (iv). A suitable amount of activating agent is typically at least 1 mole, and preferably 1 to 5 moles per mole of Compound (13). When WSC is used as an activating agent, the addition of 1-hydroxybenzotriazol to the reaction system allows the reaction to proceed advantageously. The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 90 hours.

When the method in which a carboxylic acid halide is reacted with Amine (13), mentioned above as one of the other methods (iv), is employed, the reaction is performed in the presence of a basic compound in a suitable solvent. Examples of usable basic compounds include a wide variety of known basic compounds, such as those for use in the Schotten-Baumann reaction described above. In addition to those usable in the mixed acid anhydride method, usable solvents include alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; acetonitrile; pyridine; acetone; and water. The ratio of the carboxylic acid halide to Amine (13) is not limited, and can be suitably selected from a wide range. It is typically suitable to use, for example, at least about 1 mole, and preferably about 1 to about 5 moles of the carboxylic acid halide per mole of Amine (13). The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 30 hours.

The amide bond formation reaction shown in Reaction Formula 11 can also be performed by reacting Carboxylic Acid (14) with Amine (13) in the presence of a phosphorus compound serving as a condensing agent, such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis (2-oxo-3-oxazolidinyl)phosphinic chloride, or the like.

The reaction is performed in the presence of a solvent and a basic compound usable for the method in which a carboxylic acid halide is reacted with Amine (13), typically at about −20 to about 150° C., and preferably at about 0 to about 100° C., and is typically completed in about 5 minutes to about 30 hours. It is suitable to use each of the condensing agent and Carboxylic Acid (14) in amounts of at least about 1 mole, and preferably about 1 to about 2 moles, per mole of Amine (13).

The reaction converting the compound of Formula (15) to the compound of Formula (16) can be performed by, for example, [1] reducing the compound of Formula (15) in a suitable solvent using a catalytic hydrogenation reducing agent, or [2] reducing the compound of Formula (15) in a suitable inert solvent using a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.

When Method [1] in which a catalytic hydrogenation reducing agent is used, examples of usable solvents are water; acetic acid; alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide; and mixtures thereof. Examples of usable catalytic hydrogenation reducing agents include palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum black, platinum oxide, copper chromite, and Raney nickel. The reducing agent is typically used in an amount of about 0.02 times to about equal to the weight of the compound of Formula (15). The reaction temperature is typically about −20 to about 150° C., and preferably about 0 to about 100° C. The hydrogen pressure is typically about 1 to 10 atm. The reaction is typically completed in about 0.5 to about 100 hours. An acid such as hydrochloric acid may be added to the reaction.

When Method [2] above is used, a mixture of iron, zinc, tin, or tin (II) chloride, with a mineral acid such as hydrochloric acid or sulfuric acid; or a mixture of iron, iron (II) sulfate, zinc, or tin, with an alkali metal hydroxide such as sodium hydroxide, a sulfide such as ammonium sulfide, aqueous ammonia solution, or an ammonium salt such as ammonium chloride, can be used as a reducing agent. Examples of inert solvents are water; acetic acid; alcohols such as methanol and ethanol; ethers such as dioxane; and mixtures thereof. Conditions for the reduction reaction can be suitably selected according to the reducing agent to be used. For example, when a mixture of tin (II) chloride and hydrochloric acid is used as a reducing agent, the reaction is advantageously performed at about 0 to about 150° C. for about 0.5 to about 10 hours. A reducing agent is used in an amount of at least 1 mole, and preferably about 1 to 5 moles, per mole of the compound of Formula (15).

The reaction converting the compound of Formula (16) to the compound of Formula (17) is performed under the same reaction conditions as those for the reaction of the compound of Formula (13) with the compound of Formula (14).

The reaction of the compound of Formula (17) with the compound of Formula (11) is performed under the same reaction conditions as those for the reaction of the compound of Formula (1 g) with the compound of Formula (11) in Reaction Formula 8.

wherein R¹, R^(2a), R⁴, R⁹, X¹, Y¹ and Y² are the same as above.

The reaction of the compound of Formula (19) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.

When R¹ and/or R⁴ is hydrogen in the reaction of the compound of Formula (19) with the compound of Formula (12), the hydrogen atom may be replaced with R^(2a).

The compound of Formula (18) can also be produced according to the process shown in the following Reaction Formula 13.

wherein R¹, R², R³, R⁴, R⁹, Y¹ and Y² are the same as above.

The reaction of the compound of Formula (20) with the compound of Formula (21) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (13) with the compound of Formula (14) shown in Reaction Formula 11 above.

wherein R¹, R², R³, R⁴, R⁹, Y¹ and Y² are the same as above; and Tf is trifluoromethanesulfonyl (CF₃SO₂—).

The reaction converting the compound of Formula (18) to the compound of Formula (22) can be performed in a suitable solvent in the presence of an acid.

Examples of solvents include water; lower (C₁₋₆) alcohols such as methanol, ethanol, and isopropanol; ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; aliphatic acids such as formic acid and acetic acid; sulfonic acids such as p-toluenesulfonic acid; Lewis acids such as boron fluoride, aluminium chloride, and boron tribromide; iodides such as sodium iodide and potassium iodide; and mixtures of these iodides and Lewis acids.

The reaction is performed typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 0.5 to about 25 hours. The amount of acid is typically about 1 to about 10 moles, and preferably about 1 to about 2 moles, per mole of the compound of Formula (18).

The reaction converting the compound of Formula (22) to the compound of Formula (23) is performed by reacting the compound of Formula (22) with trifluoromethanesulfonic anhydride in a suitable solvent, in the presence or absence of a basic compound.

Examples of solvents include ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof. Examples of basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO).

The reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.

wherein R¹, R², R³, R⁴, Tf, Y¹ and Y² are the same as above; M is a metal, for example, Na, K, Ag, Zu, Cu, and the like; and X is a positive number.

The reaction converting the compound of Formula (23) to the compound of Formula (4) can be performed by reacting the compound of Formula (23) with a cyano metal in a suitable solvent, in the presence of a catalyst.

Examples of metal cyanides (M(CN)_(x)) include sodium cyanide, potassium cyanide, silver cyanide, zinc cyanide, and cuprous cyanide.

Examples of solvents usable in this reaction include water; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethylether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C₁₋₆) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile; pyridine; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.

Examples of catalysts include palladium compounds such as tetrakis (triphenylphosphine) palladium (0); dichlorobis (triphenylphosphine) palladium (II); and tris (dibenzylideneacetone) dipalladium (0).

A ligand such as 1,1′-bis (diphenylphosphino) ferrocene or zinc dust may be added, as required, in order to promote the reaction.

The catalyst can be typically used in an amount of 0.01 to 1 mole, and preferably 0.01 to 0.5 moles, per mole of the compound of Formula (23).

The metal cyanide can be typically used in an amount of at least 1 mole, and preferably 1 to 3 moles, per mole of the compound of Formula (23).

The reaction is typically performed at room temperature to 200° C., and preferably at about room temperature to about 150° C. The reaction is typically completed in about 1 hour to about 1 week.

The reaction converting the compound of Formula (4) to the compound of Formula (10) is performed in a suitable solvent, in the presence of a reducing agent.

Examples of solvents include aliphatic acids such as formic acid; ethers such as dioxane, tetrahydrofuran, diethylether, and diethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.

Examples of reducing agents include alkylaluminum hydrides such as diisobutylaluminum hydride; and Raney nickel. The reducing agent is typically used in an amount at least equal to, and preferably from an equal weight to 5 times the weight of the compound of Formula (4).

The reaction is typically performed at room temperature to 200° C., and preferably at about room temperature to about 150° C. The reaction is typically completed in about 0.5 to about 20 hours.

wherein R¹, R², R³, R⁴, Tf, Y¹ and Y² are the same as above; and R¹¹ is lower alkyl.

Examples of “lower alkyl” represented by R¹¹ include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, and ethyl.

The reaction converting the compound of Formula (23) and the compound of Formula (24) to the compound of Formula (25) can be performed in a suitable solvent, in the presence of a catalyst.

Examples of usable solvents include water; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethylether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme, and diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C₁₋₆) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile; pyridine; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.

Preferable as the catalyst are palladium compounds, for example, tetrakis(triphenylphosphine)palladium (0); dichlorobis(triphenylphosphine)palladium (II); and the like. The catalyst is typically used in an amount of about 0.01 to about 1 mole, and preferably about 0.01 to about 0.5 moles, per mole of the compound of Formula (23).

Further, a basic compound such as triethylamine, pyridine, may be added, as required.

The reaction temperature is not limited, and the reaction is usually carried out under conventional conditions.

The reaction converting the compound of Formula (25) to the compound of Formula (26) can be performed by catalytic reduction of the compound of Formula (25) in a suitable solvent in a hydrogen atmosphere.

Known hydrogenolysis methods can be widely employed in hydrogenolysis. Examples of such hydrogenolysis methods include chemical reduction and catalytic reduction.

Catalysts suitable for use in catalytic reduction include platinum catalysts, such as platinum plates, spongy platinum, platinum black, colloid platinum, platinum oxide, and platinum wires; palladium catalysts, such as spongy palladium, palladium black, palladium oxide, palladium carbon, palladium/barium sulfate, and palladium/barium carbonate; nickel catalysts, such as reduced nickel, nickel oxide, and Raney nickel; cobalt catalysts, such as reduced cobalt and Raney cobalt; and iron catalysts, such as reduced iron.

The amount of the catalyst used for catalytic reduction is not limited, and may be an amount generally used.

The reaction temperature is typically 0 to 120° C., preferably room temperature to about 100° C., and more preferably room temperature to 80° C. The reaction time is typically 30 minutes to 24 hours, preferably 30 minutes to 10 hours, and more preferably 30 minutes to 4 hours.

The reaction converting the compound of Formula (26) to the compound of Formula (5) can be performed by hydrolysis of the compound (26).

This hydrolytic reaction is performed in a suitable solvent or without any solvent, in the presence of an acid or basic compound.

Examples of solvents include water; lower (C₁₋₆) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.

Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and like sulfonic acids. These acids may be used singly or in a combination of two or more.

Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These basic compounds can be used singly or in a combination of two or more.

The hydrolytic reaction advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 150° C. The reaction is typically completed in about 10 minutes to about 30 hours.

wherein R¹, R², R³, R⁴, Tf, Y¹ and Y² are the same as above; and A^(1b) is lower alkylene.

Examples of “lower alkylene” represented by A^(1b) include alkylene groups with 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.

The reaction converting the compound of Formula (23) and the compound of Formula (27) to the compound of Formula (28) can be performed in a suitable solvent, in the presence of a copper halide and a palladium catalyst.

Examples of solvents include ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.

Examples of copper halides include copper (I) chloride, copper (I) bromide, and copper (I) iodide.

Examples of palladium catalysts include palladium compounds such as tetrakis(triphenylphosphine)palladium (0); and dichlorobis(triphenylphosphine)palladium (II).

A basic compound may be added, as required. Examples of basic compounds include triethylamine, diisopropylethylamine, pyridine, and diethylamine. The basic compound can be typically used in an amount of 0.01 to 10 mole, and preferably 0.01 to 1 moles, per mole of the compound of Formula (23).

The reaction advantageously proceeds typically at about 0 to about 200° C., and preferably at about 0 to about 180° C. The reaction is typically completed in about 10 minutes to about 30 hours.

The reaction converting the compound of Formula (28) to the compound of Formula (7) can be performed under the same reaction conditions as those for the reaction converting the compound of Formula (25) to the compound of Formula (26) shown in Reaction Formula 16 above.

wherein R⁶, R⁷, R⁸, X_(A), X_(B), and X¹ are the same as above.

The reaction of the compound of Formula (3a) with the compound of Formula (8) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1d) with the compound of Formula (8) shown in Reaction Formula 5 above.

The reaction of the compound of Formula (3a) with the compound of Formula (9) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above.

The compound of Formula (3), which is used as a starting material, can be easily prepared by the process shown in the following reaction formula.

wherein R^(7b) is a nitrogen-containing heterocyclic group optionally having one or more substituents; and X_(B1) is lower alkylene.

Examples of R^(7b) include, among groups represented by the group R⁷ mentioned above, groups obtained by removing hydrogen from saturated or unsaturated, monocyclic or polycyclic, heterocyclic compounds having an N—H bond, and groups optionally having one or more substituents.

Examples of “lower alkylene” represented by X_(B1) include alkylene groups with 2 to 4 carbon atoms, such as ethylene and trimethylene.

The reaction of the compound of Formula (29) with the compound of Formula (30) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.

The reaction converting the compound of Formula (31) to the compound of Formula (3d) can be performed under the same reaction conditions as those for the reaction converting the compound of Formula (7) to the compound of Formula (1c) shown in Reaction Formula 4 above.

wherein R^(7b) is the same as above; X_(B2) is lower alkylene; and R¹² and R¹³ are each independently lower alkyl, or R¹² and R¹³ are linked to form lower alkylene.

Examples of “lower alkyl” represented by R¹² and R¹³ include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, and n-propyl. Examples of “lower alkylene” formed by R¹² and R¹³ when they are linked include alkylene groups with 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.

Examples of “lower alkylene” represented by X_(B2) include alkylene groups with 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, and tetramethylene.

The reaction of the compound of Formula (29) with the compound of Formula (32) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.

The reaction converting the compound of Formula (33) to the compound of Formula (8a) can be performed by hydrolysis of the compound (33).

This hydrolytic reaction is performed in a suitable solvent or without any solvent, in the presence of an acidic compound.

Examples of solvents include water; lower (C₁₋₆) alcohols such as methanol, ethanol, isopropanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethylether, dioxane, tetrahydrofuran, monoglyme, and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; dimethyl sulfoxide; N,N-dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof.

Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid (PPTS), and like sulfonic acids. These acids may be used singly or in a combination of two or more.

The hydrolytic reaction advantageously proceeds typically at about 0 to about 100° C., and preferably at about 0 to about 80° C. The reaction is typically completed in about 10 minutes to about 30 hours.

wherein A^(1b) is the same as above; and Ms is methanesulfonyl (CH₃SO₂—).

The reaction converting the compound of Formula (34) to the compound of Formula (35) is performed by methanesulfonylation (mesylation) of the compound of Formula (34) using a conventional method. Typically, the compound of Formula (35) can be produced by reacting the compound of Formula (34) with trifluoromethanesulfonic anhydride in a suitable solvent (e.g., dichloromethane), in the presence of a basic compound (e.g., triethylamine).

The reaction converting the compound of Formula (35) to the compound of Formula (36) is performed by iodination of the compound of Formula (35) with an iodinating agent such as sodium iodide, in a suitable solvent (e.g., acetone).

The reaction converting the compound of Formula (36) to the compound of Formula (27) can be performed by reacting the compound of Formula (36) with potassium phthalimide in a suitable solvent (e.g., N,N-dimethylformamide).

Alternatively, the compound of Formula (27) can be directly produced by reacting the compound of Formula (34) with phthalimide under the Mitsunobu reaction conditions (e.g., using diethyl azodicarboxylate (DEAD) and triphenylphosphine).

The compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.

In addition, compounds in the form in which a solvate (for example, a hydrate, ethanolate, etc.) was added to the starting material compounds and object compounds shown in each of the reaction formulae are included in each of the formulae.

The compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.

The starting material compounds and object compounds represented by each of the reaction formulae can be used in an appropriate salt form.

Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a general purification procedure such as column chromatography, recrystallization, etc.

Among the compounds of the present invention, those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.

Among the compounds of the present invention, those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.

In the compound of the present invention, one or more atoms can be substituted with one or more isotopic atoms. Examples of the isotopic atoms include deuterium (²H), tritium (³H), ¹³C, ¹⁴N, ¹⁸O, etc.

The following is an explanation of pharmaceutical preparations comprising the compound of the present invention as an active ingredient.

Such pharmaceutical preparations are obtained by formulating the compound of the present invention into general pharmaceutical preparations, using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.

The form of such pharmaceutical preparations can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.

To form tablets, any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc.

Such tablets may be coated with general coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.

To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.

To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.

To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic with blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain general solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.

The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is typically preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.

The route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.

For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with general injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.

The dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is typically about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.

Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.

When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.

The compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels. Thus, the compound of the invention has characteristics as an atrial-selective K⁺ channel-blocking agent.

Therefore, the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents. The compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia). The compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm). The compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.

The compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).

2. Second Invention (Amino Compound)

The present inventors conducted extensive research to develop a compound that blocks the I_(Kur) current (Kv1.5 channel) and/or the I_(KA)C_(h) current (GIRK1/4 channel) potently and more selectively than other K⁺ channels. As a result, the inventors found that a novel amino compound represented by General Formula (1) below could be the desired compound. The present invention has been accomplished based on the above findings.

The present invention provides amino compounds, and pharmaceutical compositions comprising the amino compounds as summarized in items 1 to 7 below.

Item 1. An amino compound represented by General Formula (1):

or a salt thereof, wherein R¹ and R² are each independently hydrogen or organic group; X_(A) and X_(B) are each independently a bond, alkylene, alkenylene, —CO—, —SO₂—, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C(═S)—, —SO₂—, —CO—, —O—, —NH—, —CONH— and —SO₂NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in X_(A) and X_(B) is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl; A¹ is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo; R³ is (i) a heterocyclic group which is optionally substituted with one or more substituents, or (ii) an aryl group substituted with one or more substituents selected from the group consisting of oxo, lower alkyl, carboxyl, halo-lower alkyl, lower alkanoyl lower alkyl, phenyl lower alkyl, cyclo lower alkyl, lower alkoxy, halo lower alkoxy, phenyl lower alkoxy, phenoxy, cyano, hydroxyl, halogen, nitro, lower alkyl thio, lower alkanoyl, lower alkoxy carbonyl, lower alkenyl, phenyl, triazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzo[d]oxazolyl, benzo[d]thiazolyl and the group represented by General Formula (2):

wherein Y is a bond, lower alkylene, or —CO—; R⁴ and R⁵ are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, or lower alkanoyl; or R⁴ and R⁵ may be linked to form a ring together with the neighboring nitrogen, and the ring may optionally have one or more substituents.

Item 2. A pharmaceutical composition comprising an amino compound represented by Formula (1) or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.

Item 3. A pharmaceutical composition according to Item 1 for preventing and/or treating arrhythmia.

Item 4. An amino compound represented by Formula (1) or a salt thereof according to Item 1 for use in the pharmaceutical composition.

Item 5. Use of an amino compound represented by Formula (1) or a salt thereof according to Item 1 as a pharmaceutical composition.

Item 6. Use of an amino compound represented by Formula (1) or a salt thereof according to Item 1 for the production of a pharmaceutical composition.

Item 7. A method of preventing and/or treating arrhythmia, comprising administering to a patient an amino compound represented by Formula (1) or a salt thereof according to Item 1.

The groups represented by, or substituents of, R¹, R², R³, R⁴, R⁵, A¹, X_(A), X_(B) and Y in the specification are described below.

The term “one or more” may be preferably 1 to 6, more preferably 1 to 3.

Examples of “lower alkyl” include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.

Examples of “alkylene” include linear or branched alkylene groups having 1 to 12 carbon atoms, such as the following “lower alkylene”, heptamethylene, octamethylene, decamethylene, and dodecamethylene.

Examples of “lower alkylene” include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene, and hexamethylene.

Examples of “alkenylene” include linear or branched alkenylene groups having 2 to 12 carbon atoms, such as the following “lower alkenylene”, heptenylene, octenylene, decenylene, and dodecenylene.

Examples of “lower alkenylene” include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as ethenylene, propenylene, butenylene, pentenylene, and hexenylene.

Examples of “lower alkylidene” include linear or branched alkylidene groups having 1 to 6 carbon atoms, such as methylidene, ethylidene, propylidene, and butylidene.

Examples of “cyclo lower alkyl” include linear or branched cyclo alkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Examples of “lower alkoxy” include linear or branched alkoxy groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.

Examples of “halogen” include fluorine, chlorine, bromine, and iodine.

Examples of “lower alkylenedioxy” include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.

Examples of “lower alkanoyl” include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.

Examples of “lower alkoxycarbonyl” include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.

Examples of “aralkyl group” include lower alkyl group substituted with one or more aryl groups, such as benzyl and phenethyl.

Examples of “organic group” include lower alkyl, lower alkoxy, cyclo lower alkyl, amino, lower alkyl thio, aryl, and heterocyclic group, each of which is optionally substituted.

Examples of “aryl group” include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, naphthyl and tetrahydronaphthyl, indenyl, and dihydroindenyl.

Examples of “heterocyclic group” include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. More preferable examples of heterocyclic groups include the following (a) to (o):

(a) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;

(b) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, 1,4-diazepanyl, etc.;

(c) saturated or unsaturated condensed 7- to 14-membered heterocyclic groups containing 1 to 5 nitrogen atom(s), for example, decahydroquinolyl, indolyl, dihydroindolyl (e.g., 2,3-dihydroindolyl, etc.), isoindolyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazolyl, etc.), quinolyl, dihydroquinolyl (e.g. 1,4-dihydroquinolyl, 1,2-dihydroquinolyl, etc.), tetrahydroquinolyl (1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, 1,2-dihydroisoquinolyl, etc.), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.), indazolyl, benzotriazolyl (e.g. benzo[d][1,2,3]triazolyl, etc.), tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-c]pyridyl, etc.,), naphthyridinyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolopyridyl (e.g., pyrazolo[2,3-a]pyridyl, etc.) tetrahydropyridoindolyl (e.g., 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, etc.), etc.;

(d) saturated or unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s), for example, furyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl, etc.), tetrahydrofuryl, etc.;

(e) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 oxygen atom(s), for example, benzofuryl, dihydrobenzofuryl (e.g. 2,3-dihydrobenzo[b]furyl, etc.), chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl, etc.), benzodioxolyl (benzo[1,3]dioxolyl, etc.), etc.;

(f) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

(g) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.;

(h) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzisoxazolyl, dihydrobenzoxazinyl (e.g., 2,3-dihydrobenz-1,4-oxazinyl, etc.), furopyridyl (e.g., furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, etc.), furopyrrolyl (e.g., furo[3,2-b]pyrrolyl etc.) etc.;

(i) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), isothiazolyl, etc.;

(j) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;

(k) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, thienyl, etc.;

(l) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 sulfur atom(s), for example, benzothienyl (e.g. benzo[b]thienyl), etc.;

(m) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzo[d]isothiazolyl, 2,3-dihydro benzo[d]isothiazolyl, benzothiadiazolyl, thienopyridyl (e.g., thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, etc.), imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl, etc.), dihydroimidazothiazolyl (e.g., 2,3-dihydroimidazo[2,1-b]thiazolyl, etc.), thienopyrazinyl (e.g., thieno[2,3-b]pyrazinyl, etc.), etc.;

(n) saturated or unsaturated 7- to 12-membered heterocyclic spiro groups containing 1 to 2 nitrogen atom(s), for example, azaspiroundecanyl (e.g., 3-azaspiro[5.5]undecanyl), etc.; and

(O) saturated 7- to 12-membered hetero bicyclic groups containing 1 to 3 nitrogen atom(s), for example, azabicyclooctanyl (e.g., (1R,5S)-8-azabicyclo[3.2.1]octanyl), etc;

wherein said heterocyclic group may be substituted by one or more suitable substituents.

Substituents of “aryl group which is optionally substituted” represented by R¹ and R² are each independently one or more substituents selected from the group consisting of:

(a1) cyano; (a2) hydroxyl; (a3) halogen; (a4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, hydroxyl, imidazolyl, morpholinyl, triazolyl and phenyl; (a5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of halogen, amino, lower alkyl amino and phenyl; (a6) pyridyl; (a7) thienyl; (a8) piperazinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and halo phenyl lower alkyl; (a9) phenyl; (a10) pyrazolyl optionally substituted with one or more lower alkyl; (a11) pyrimidinyl optionally substituted with one or more lower alkyls; (a12) piperidyl optionally substituted with one or more lower alkyls; (a13) furyl; (a14) carboxy; (a15) lower alkoxycarbonyl; (a16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, phenyl, lower alkanoyl and lower alkylsulfonyl; (a17) lower alkylthio; (a18) triazolyl; (a19) imidazolyl; (a20) pyrrolidinyl optionally substituted with one or more oxos; (a21) lower alkylsulfonyl; (a22) lower alkylenedioxy optionally substituted with one or more halogens; (a23) nitro; (a24) oxazolyl; (a25) thiazolyl optionally substituted with one or more lower alkyls; (a26) lower alkanoyl; (a27) sulfo; (a28) carbamoyl optionally substituted with one or two lower alkyls; (a29) phenoxy; (a30) isoxazolyl; (a31) pyrrolyl; (a32) lower alkenyl; (a33) cyclo lower alkyl; (a34) benzo[d]oxazolyl; and (a35) oxo.

Substituents of “heterocyclic group which is optionally substituted” represented by R¹ and R² are each independently one or more substituents selected from the group consisting of:

(h1) oxo; (h2) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, phenyl amino, cyclo lower alkyl, lower alkoxy, pyridyl, mono- or di-lower alkyl amino, hydroxyl, lower alkyl substituted isoxazolyl, 1,3-dioxolanyl, lower alkyl substituted piperidinyl, mono or di lower alkyl amino, fulyl, imidazolyl, morpholinyl, lower alkyl substituted 1,4-diazepanyl, phenyl thiazolyl, phenyl lower alkyl tetrazolyl, lower alkyl tetrazolyl, quinolyl, pyrrolyl, imidazolyl, 2,3-dihydrobenzofuryl and benzodioxolyl; (h3) cyclo lower alkyl; (h4) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of pyridyl, halo-lower alkoxy phenyl, halo phenyl, phenyl, and halo-lower alkyl phenyl; (h5) aryl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo-lower alkyl, lower alkoxy, halo lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, and cyano; (h6) aralkyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, cyano, phenyl, and oxo, on the aryl and/or lower alkyl group of aralkyl; (h7) heterocyclic group optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkanoyl, hydroxyl, halogen, carboxy, lower alkoxycarbonyl, amino, lower alkyl amino, cyano, phenyl, and oxo; (h8) hydroxyl; (h9) halogen; (h10) carboxy; (h11) lower alkanoyl; (h12) lower alkoxycarbonyl; (h13) lower alkylenedioxy; (h14) cyano; (h15) nitro; (h16) sulfo; (h17) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, mono- or di-lower alkyl amino lower alkyl, (lower alkyl)(phenyl)amino lower alkyl, lower alkyl substituted phenoxy lower alkyl, phenyl lower alkyl, cyclo lower alkyl lower alkyl, lower alkyoxy phenyl lower alkyl, lower alkyl phenyl lower alkyl, triazolyl lower alkyl, halo substituted phenyl, halo-lower alkyl substituted phenyl, halo-lower alkoxy substituted phenyl, piperazinyl lower alkyl carbonyl, phenyl lower alkyl carbonyl and lower alkoxy dihydroindenyl; (h18) lower alkylthio; (h19) lower alkylsulfonyl; (h20) lower alkenyl optionally substituted with one or more phenyls; (h21) benzo[d][1,3]dioxolyl carbonyl; (h22) 2,3-dihydroindenyl; (h23) phenoxy substituted with one or more substituents selected from the group consisting of halo-lower alkoxy and halogen; (h24) lower alkylidene substituted with one or more lower alkoxy phenyls;

Substituents of “lower alkyl group which is optionally substituted” represented by R¹ and R² are each independently one or more substituents selected from the group consisting of oxo and phenyl.

Substituents of “cyclo lower alkyl group which is optionally substituted” represented by R¹ and R² are each independently one or more substituents selected from the group consisting of lower alkyl phenyl and phenyl.

Substituents of “amino group which is optionally substituted” represented by R¹ and R² are each independently one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and phenyl lower alkyl.

Substituents of “dihydroindenyl group which is optionally substituted” represented by R¹ and R² are each independently one or more oxos.

Preferable substituents represented by R¹ and R² are each independently selected from the group consisting of the following substituents (1) to (69):

(1) hydrogen; (2) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo and phenyl; (3) cyclo lower alkyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl phenyl and phenyl; (4) phenyl optionally substituted with one or more substituents selected from the group consisting of the following (4-1) to (4-25): (4-1) cyano; (4-2) hydroxyl; (4-3) halogen; (4-4) lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, imidazolyl, hydroxyl, triazolyl (e.g, 1,2,4-triazolyl) and morpholinyl; (4-5) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of amino and lower alkyl amino; (4-6) pyridyl; (4-7) thienyl; (4-8) piperazinyl optionally substituted with one or more lower alkyls; (4-9) phenyl; (4-10) pyrazolyl optionally substituted with one or more lower alkyls; (4-11) pyrimidinyl optionally substituted with one or more lower alkyls; (4-12) piperidyl optionally substituted with one or more lower alkyls; (4-13) furyl; (4-14) carboxy; (4-15) lower alkoxycarbonyl; (4-16) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and lower alkylsulfonyl; (4-17) lower alkylthio; (4-18) triazolyl; (4-19) imidazolyl; (4-20) pyrrolidinyl optionally substituted with one or more oxos; (4-21) lower alkylsulfonyl; (4-22) lower alkylenedioxy optionally substituted with one or more halogens; (4-23) nitro; (4-24) oxazolyl; (4-25) thiazolyl optionally substituted with one or more lower alkyls; (4-26) phenoxy; and (4-27) carbamoyl optionally substituted with one or two lower alkyls; (5) naphthyl; (6) furyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, carboxy, sulfo, pyridyloxy, lower alkoxycarbonyl, and phenyl; (7) thienyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkylenedioxy, carboxy, halogen, pyridyl, lower alkoxy, lower alkoxycarbonyl, oxazolyl, and furyl; (8) imidazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl, and halogen; (9) pyrazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, halogen, phenyl optionally substituted with lower alkoxy, furyl, and thienyl; (10) oxazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl; (11) isoxazolyl optionally substituted with one or more substituents selected from the group consisting of phenyl, lower alkyl, thienyl, and furyl; (12) thiazolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with lower alkoxy, phenyl, and lower alkanoylamino; (13) pyrrolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl; (14) triazolyl optionally substituted with one or more lower alkyls; (15) pyridyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl optionally substituted with halogen, oxo, hydroxyl, lower alkoxy, halogen, pyrrolidinyl, morpholinyl, thienyl, piperazinyl lower alkyl carbonyl amino; (16) pyrimidinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and phenyl; (17) pyridazinyl; (18) pyrazinyl; (19) imidazo[2,1-b]thiazolyl optionally substituted with one or more halogens; (20) thieno[2,3-b]pyrazinyl; (21) 2,3-dihydroimidazo[2,1-b]thiazolyl optionally substituted with one or more phenyls; (22) benzothiazolyl optionally substituted with one or more lower alkyls; (23) indolyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and halogen; (24) imidazo[1,2-a]pyridyl optionally substituted with one or more lower alkyls; (25) benzothienyl optionally substituted with one or more lower alkyls; (26) benzimidazolyl optionally substituted with one or more lower alkyls; (27) 2,3-dihydrobenzo[b]furyl; (28) benzofuryl optionally substituted with one or more halogens; (29) indazolyl optionally substituted with one or more lower alkyls; (30) furo[2,3-c]pyridyl or 6,7-dihydrofuro[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl; (31) furo[3,2-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl optionally substituted with halogen, halogen, furyl, pyridyl, and phenyl optionally substituted with one or more substituents selected from the group consisting of amino and lower alkoxy; (32) thieno[2,3-c]pyridyl or 6,7-dihydrothieno[2,3-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo group and lower alkyl; (33) thieno[3,2-c]pyridyl or 4,5-dihydrothieno[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl; (34) thieno[2,3-b]pyridyl; (35) benzo[1,3]dioxolyl optionally substituted with one or more halogens; (36) benzisoxazolyl; (37) pyrazolo[2,3-a]pyridyl; (38) indolizinyl; (39) 2,3-dihydroindolyl optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkyl, and lower alkanoyl; (40) isoquinolyl or 1,2-dihydroisoquinolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, lower alkoxy and oxo; (41) 1,2,3,4-tetrahydroisoquinolyl optionally substituted with one or more oxos; (42) 1,2-dihydroquinolyl optionally substituted with one or more substituents selected from the group consisting of lower alkoxy and oxo; (43) 1,2,3,4-tetrahydroquinolyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkoxy; (44) quinolyl optionally substituted with one or more substituents selected from the group consisting of amino optionally substituted with one or two lower alkyl, lower alkoxy, lower alkyl, and oxo; (45) chromanyl optionally substituted with one or more lower alkyls; (46) 5,6,7,8-tetrahydroisoquinolyl optionally substituted with one or more oxos; (47) 3,4-dihydroisoquinolyl optionally substituted with one or more oxos; (48) naphthyridinyl; (49) 1,4-benzodioxanyl; (50) cinnolinyl; (51) quinoxalinyl; (52) 2,3-dihydrobenz-1,4-oxazinyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and oxo; (53) 2,3-dihydroindenyl optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkoxy; (54) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl and phenyl lower alkyl; (55) lower alkoxy; (56) lower alkylthio; (57) decahydroquinolyl; (58) piperazinyl optionally substituted with one or more substituents selected from the group consisting of (58-1) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, lower alkoxy, 1,3-dioxolanyl, lower alkyl-substituted piperidyl, furyl, imidazolyl, phenyl amino, phenyl-substituted thiazolyl, phenyl lower alkyl-substituted tetrazolyl, lower alkyl-substituted tetrazolyl, quinolyl, pyrrolyl, mono- or di-lower alkyl amino, pyridyl and benzo[d][1,3]dioxolyl; (58-2) oxo; (58-3) halo-lower alkyl substituted phenyl amino; (58-4) cyclo lower alkyl; (58-5) 2,3-dihydroindenyl; (58-6) phenyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo-lower alkyl and halo-lower alkoxy; and (58-7) phenyl lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, halo-lower alkyl, halo-lower alkoxy and pyridyl, on the benzene ring and/or lower alkyl of phenyl lower alkyl; (59) 1,4-diazepanyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl, pyridyl and morpholinyl lower alkyl; (60) piperidyl optionally substituted with one or more substituents selected from the group consisting of: (60-1) lower alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, mono- or di-lower alkylamino, 2,3-dihydrobenzofuryl and imidazolyl; (60-2) amino optionally substituted with one or two substituents selected from the group consisting of lower alkyl, halo-phenyl, halo-lower alkoxy-substituted phenyl, mono- or di-lower alkyl amino lower alkyl, lower alkyl-substituted phenoxy lower alkyl, phenyl lower alkyl, phenyl lower alkyl carbonyl, cyclo lower alkyl lower alkyl, lower alkoxy phenyl lower alkyl, 1,2,4-triazolyl lower alkyl, pyridyl phenyl, (phenyl)(lower alkyl)amino lower alkyl, lower alkoxy-substituted 2,3-dihydro-1H-indenyl and lower alkyl phenyl lower alkyl; (60-3) lower alkoxy optionally substituted with one or more substituents selected from the group consisting of phenyl, halo-phenyl, halo-lower alkoxy-substituted phenyl, halo-lower alkyl substituted phenyl and pyridyl; (60-4) phenoxy optionally substituted with one or more substituents selected from the group consisting of halogen, and halo-lower alkoxy; (60-5) phenyl lower alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, lower alkoxy and amino, on the benzene ring and/or lower alkyl of phenyl lower alkyl; (60-6) lower alkoxy phenyl lower alkylidene; (60-7) phenyl imidazolyl; (60-8) phenyl morpholinyl; and (60-9) phenyl; (61) morpholinyl optionally substituted with one or more mono- or di-lower alkyl amino-substituted piperidyl lower alkyls; (62) benzo[d][1,2,3]triazolyl optionally substituted with one or more lower alkyls; (63) 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl; (64) 2,3,4,9-tetrahydropyrido[3,4-b]indolyl); (65) 3-azaspiro[5,5]undecanyl; (66) 8-azabicyclo[3,2,1]octanyl; (67) tetrahydro-2H-pyranyl; (68) furo[3,2-b]pyrrolyl optionally substituted with one or more lower alkyls; and (69) tetrahydrofuryl.

Preferable examples of “aryl group which is optionally substituted” for R¹ and R² include the substituents (4), (5) and (53).

Preferable examples of “heterocyclic group which is optionally substituted” for R¹ and R² include the substituents (6) to (52) and (57) to (69).

Examples of X_(A) and X_(B) include a bond, lower alkylene, lower alkenylene, —CO—, —SO₂—, -lower alkylene-SO₂—, -lower alkylene-CO—, -lower alkenylene-CO—, -lower alkylene-CO—N(lower alkyl)-lower alkylene-, —N(lower alkyl)-lower alkylene-, —CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-, —N(phenyl lower alkyl)-lower alkylene-, —CO-lower alkylene-CO—, —CO—NH-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-, -lower alkylene-N(lower alkyl)-lower alkylene-O—, -lower alkylene-NH-lower alkylene-, -lower alkylene-SO₂—NH-lower alkylene-, —N(lower alkyl)-CO-lower alkylene-, —N(lower alkyl)-lower alkylene-CO—, —N(lower alkyl)-lower alkylene-N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—, —NH—CO—, —NH—CO-lower alkylene-, —NH-lower alkylene-, —O-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —O-lower alkylene-CO—, —NH-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —S-lower alkylene-CO—N(lower alkyl)-lower alkylene-, —SO₂—N(lower alkyl)-lower alkylene-, —SO₂—NH-lower alkylene-, -lower alkenylene-CO—N(lower alkyl)-lower alkylene-, —N(phenyl)-lower alkylene-CO—N(lower alkyl)-lower alkylene-, and —CO-lower alkylene-O—CO—.

Either of the two bonds in X_(A) may be bonded to R¹ or N, and either of the two bonds in X_(B) may be bonded to R² or N.

Examples of “lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo” represented by A¹ are C₁₋₆ alkylene and —CO—C₂₋₆ alkylene-.

Examples of heterocyclic groups of “heterocyclic group which is optionally substituted” represented by R³ include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, isoquinolyl, 1,2-dihydroisoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, quinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, indolyl, 2,3-dihydroindolyl, isoindolyl, 1,3-dihydroisoindolyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, benzo[d]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3,4,5-tetrahydrobenz[f]1,4-thiazepinyl, 1,7-naphthyridinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl, benzo[d][1,3]oxathiolyl, 2H-chromenyl, 2H-pyranyl, benzofuryl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl, 2,3,4,5-tetrahydrobenzo[e][1,4]diazepinyl, 2,3,4,5-tetrahydrobenzo[b]azepinyl, 2,3-dihydrobenzo[d]thiazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3,4,5-tetrahydrobenzo[c]azepinyl, 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepinyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, benzo[c][1,2,5]oxadiazolyl, 2H-pyranyl, 3,4-dihydroisoquinolyl, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepinyl, 1,2,3,5-tetrahydrobenzo[e][1,4]oxazepinyl, 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinyl, dibenzo[b,d]furyl, 9H-carbazolyl, benzo[c][1,2,5]oxadiazolyl, 1,2,3,4,5,6-hexahydrobenzo[b]azocinyl, 2,3-dihydrobenzofuryl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 2,4-dihydro-1H-benzo[d][1,3]oxazinyl, and benzo[b]thiophenyl.

Examples of substituents of “substituted heterocyclic group” represented by R³ include the substituents (h1) to (h17) and (h20) to (h24), which are mentioned as substituents of heterocyclic groups represented by R¹ and R². Among these, preferable substituents are (h1), (h2), (h5), (h6), (h8), (h10), (h11), (h12) and (h20), and more preferable substituents are (h1) and/or (h2).

Examples of aryl groups of “aryl group which is substituted” represented by R³ include those as defined above.

When R⁴ and R⁵ in General Formula (2) are linked to form a ring together with the neighboring nitrogen, examples of the group —N R⁴R⁵ include the following:

Each of the ring may optionally have one or more substituents selected from the group consisting of oxo; lower alkyl; phenyl lower alkyl; halo-phenyl lower alkyl; and amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, phenyl and halo-phenyl.

The amino compound of the present invention represented by General Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification. For example, the amino compound or its salt can be produced according to the processes shown in the following reaction formulae.

wherein R¹, R², R³, X_(A), X_(B) and A¹ are the same as above; and X¹ is a leaving group.

The reaction of the compound of Formula (3) with the compound of Formula (4) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound.

Examples of the leaving groups represented by X¹ include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkanesulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C₁₋₆) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.

A wide variety of known basic compounds can be used as the basic compound. Examples of usable basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine, tripropylamine, pyridine, quinoline, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.

The above reaction may be performed by adding as a reaction accelerator an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.

The compound of Formula (4) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (3).

The amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (3).

The reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.

wherein R¹, R², R³, X_(A) and A¹ are the same as above; and R^(2a) is hydrogen or lower alkyl.

Examples of lower alkyl groups represented by R^(2a) include linear or branched alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl.

The reaction between the compound of Formula (1b) and the compound of Formula (5) is performed, for example, in an inert solvent or suitable solvent, in the presence of a reducing agent.

Examples of usable solvents include water; lower (C₁₋₆) alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; aliphatic acids such as acetonitrile, formic acid, and acetic acid; ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme, and diglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixtures thereof.

Examples of reducing agents include aliphatic acids such as formic acid; aliphatic acid alkali metal salts such as sodium formate; hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium trimethoxyborohydride, and lithium aluminium hydride; and mixtures thereof, or mixtures of aliphatic acids or aliphatic acid alkali metal salts and hydride reducing agents; and catalytic hydrogenation reducing agents such as palladium black, palladium carbon, platinum oxide, platinum black, and Raney nickel.

When an aliphatic acid such as formic acid, or an aliphatic acid alkali metal salt such as sodium formate is used as a reducing agent, a suitable reaction temperature is typically about room temperature to about 200° C., and preferably about 50 to about 150° C. The reaction is typically completed in about 10 minutes to about 10 hours. Preferably, the aliphatic acid or aliphatic acid alkali metal salt is used in large excess relative to the compound of Formula (1b).

When a hydride reducing agent is used, a suitable reaction temperature is typically about −80 to about 100° C., and preferably about −80 to about 70° C. The reaction is typically completed in about 30 minutes to about 60 hours. The hydride reducing agent is typically used in an amount of about 1 to about 20 moles, and preferably about 1 to about 10 moles, per mole of the compound of Formula (1b). Particularly when lithium aluminium hydride is used as a hydride reducing agent, it is preferable to use as a solvent an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme; or an aromatic hydrocarbon such as benzene, toluene, or xylene. To the reaction system of the reaction may be added an amine such as trimethylamine, triethylamine, or N-ethyldiisopropylamine; or a molecular sieve such as molecular sieve 3A (MS-3A) or molecular sieve 4A (MS-4A).

When a catalytic hydrogenation reducing agent is used, the reaction is typically performed at about −30 to about 100° C., and preferably about 0 to about 60° C., in a hydrogen atmosphere at typically about atmospheric pressure to about 20 atm, and preferably at about atmospheric pressure to about 10 atm, or in the presence of a hydrogen doner such as formic acid, ammonium formate, cyclohexene, or hydrazine hydrate. The reaction is typically completed in about 1 to about 12 hours. The catalytic hydrogenation reducing agent is typically used in an amount of about 0.1 to about 40 wt %, and preferably about 1 to about 20 wt %, based on the compound of Formula (1b).

In the reaction of the compound of Formula (1b) and the compound of Formula (5), the compound of Formula (5) is typically used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the compound of Formula (1b).

The compound of Formula (5) may also be a hydrated compound wherein a water molecule is attached to a carbonyl group.

wherein R¹, R², R³, X_(A), X_(B), A¹ and X¹ are the same as above.

The reaction of the compound of Formula (1b) with the compound of Formula (6) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.

Alternatively, the reaction of the compound of Formula (1b) with the compound of Formula (6) can be performed by the known “Ullmann condensation”, “Palladium coupling reaction”, etc. The reaction can be preferably adopted especially when X_(B) is a bond and R² is aryl or heterocyclic (especially unsaturated heterocyclic) group optionally substituted. For example, the reaction can be carried out in a solvent (e.g., toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO)), in the presence of transition metal compound (e.g., Pd(OAc)₂, Pd₂(dba)₃ and copper iodide), a basic compound (e.g., sodium tert-butoxide, K₃PO₄ and Cs₂CO₃), and if necessary a phosphine (e.g., xantphos, tri-tert-butylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tetrafluoroborate, N,N′-dimethylethylenediamine, and L-proline).

The reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.

The compound of Formula (3), which is used as a starting material, can be easily prepared by the process shown in the following reaction formula.

wherein R¹, R², R^(2a), X_(A), X_(B) and X¹ are the same as above.

The reaction of the compound of Formula (3a) with the compound of Formula (7) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1b) with the compound of Formula (5) shown in Reaction Formula 2 above.

The reaction of the compound of Formula (3a) with the compound of Formula (6) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.

wherein R¹, R², R³, X_(A), X_(B) and A¹ are the same as above.

The reaction of the compound of Formula (8) with the compound of Formula (9) can be performed by the known “Mitsunobu reaction” conditions (e.g., using diethyl azodicarboxylate (DEAD) and triphenylphosphine).

wherein R¹, R², R³, X_(A), X_(B), X¹ and A¹ are the same as above.

The reaction of the compound of Formula (10) with the compound of Formula (9) can be performed by the known O-alkylation reaction. For example, The reaction can be performed in the presence of an inert solvent (e.g., DMF, THF, dioxane and acetonitrile) and in the presence of a basic compound (e.g., K₂CO₃ and Cs₂CO₃).

The reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.

wherein R¹, R², R³, X_(A) and X_(B) are the same as above; and A¹⁰ is a divalent residue which is obtained by removing —CH₂— from group A¹.

The reaction of the compound of Formula (3) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (1b) with the compound of Formula (5) shown in Reaction Formula 2 above,

wherein R³, X¹, X² and A¹ are the same as above.

The reaction of the compound of Formula (9) with the compound of Formula (15) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (9) with the compound of Formula (10) shown in Reaction Formula 6 above.

The reaction of the compound of Formula (9) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (9) with the compound of Formula (10) shown in Reaction Formula 6 above.

The reaction of the compound of Formula (4) with the compound of Formula (13) can be performed by the known N-alkylation reaction. For example, The reaction can be performed in the presence of an inert solvent (e.g., DMF, THF, dioxane and acetonitrile) and in the presence of a basic compound (e.g., K₂CO₃ and Cs₂CO₃).

The N-alkylation reaction temperature is not limited, and the reaction is usually carried out at ambient temperature, under warming or under heating.

The reaction converting the compound of Formula (14) to the compound of Formula (1e) can be performed by the known method. For example, The reaction can be performed in the presence of hydrazine.

wherein R¹, R², X_(A), X_(B), X¹ and A¹ are the same as above; and P is a hydroxyl-protecting group and X² is a leaving group.

Examples of hydroxyl-protecting groups represented by P include tetrahydropyran-2-yl, methoxymethyl, benzyl.

Examples of the leaving groups represented by X² include halogen atoms (e.g., chlorine, bromine, iodine, and like atoms), lower alkanesulfonyloxy (e.g., methanesulfonyloxy), halo substituted lower alkane sulfonyloxy (e.g., trifluoromethanesulfonyloxy), arylene sulfonyloxy (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy), etc.

When X¹ and X² are both halogen atoms, the halogen atom represented by X² is preferably one having an atomic number equal to or higher than that of the halogen atom represented by X¹.

The reaction of the compound of Formula (3) with the compound of Formula (12) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.

The reaction of the compound of Formula (3) with the compound of Formula (17) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (3) with the compound of Formula (4) shown in Reaction Formula 1 above.

The reaction converting the compound of Formula (18) to the compound of Formula (8) can be performed under the known deprotection method depending on the type of the protecting group (P).

The compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.

In addition, compounds in the form in which a solvate (for example, a hydrate, ethanolate, etc.) was added to the starting material compounds and object compounds shown in each of the reaction formulae are included in each of the formulae.

The compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.

The starting material compounds and object compounds represented by each of the reaction formulae can be used in an appropriate salt form.

Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a usual purification procedure such as column chromatography, recrystallization, etc.

Among the compounds of the present invention, those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.

Among the compounds of the present invention, those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.

In the compound of the present invention, one or more atoms can be substituted with one or more isotopic atoms. Examples of the isotopic atoms include deuterium (²H), tritium (³H), ¹³C, ¹⁴N, ¹⁸O, etc.

The following is an explanation of pharmaceutical preparations comprising the compound of the present invention as an active ingredient.

Such pharmaceutical preparations are obtained by formulating the compound of the present invention into usual pharmaceutical preparations, using usually employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.

The form of such pharmaceutical preparations can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.

To form tablets, any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc.

Such tablets may be coated with usual coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.

To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.

To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.

To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic with blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain usual solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.

The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is usually preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.

The route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.

For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with usual injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.

The dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is usually about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.

Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.

When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.

The compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels. Thus, the compound of the invention has characteristics as an atrial-selective K⁺ channel-blocking agent.

Therefore, the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents. The compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia). The compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm). The compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.

The compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).

3. Third Invention (Benzodiazepine Compound)

The present inventors conducted extensive research to develop a compound that blocks the I_(Kur) current (Kv1.5 channel) and/or the I_(KA)C_(h) current (GIRK1/4 channel) potently and more selectively than other K⁺ channels. As a result, the inventors found that a novel benzodiazepine compound represented by General Formula (1) below could be the desired compound. The present invention has been accomplished based on the above findings.

The present invention provides benzodiazepine compounds, and pharmaceutical compositions comprising the benzodiazepine compounds as summarized in items 1 to 7 below.

Item 1. A benzodiazepine compound represented by General Formula (1):

or a salt thereof, wherein R¹, R², R³, and R⁴ are each independently hydrogen or lower alkyl; R² and R³ may be linked to form lower alkylene; A¹ is lower alkylene optionally substituted with one or more hydroxyls; and R⁵ is an aryl or heterocyclic group, each of which is optionally substituted.

Item 2. A pharmaceutical composition comprising a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1, and a pharmacologically acceptable carrier.

Item 3. A pharmaceutical composition according to Item 2 for preventing and/or treating arrhythmia.

Item 4. A benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 for use in the pharmaceutical composition.

Item 5. Use of a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 as a pharmaceutical composition.

Item 6. Use of a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1 for the production of a pharmaceutical composition.

Item 7. A method of preventing and/or treating arrhythmia, comprising administering to a patient a benzodiazepine compound represented by Formula (1) or a salt thereof according to Item 1.

The groups represented by, or substituents of, R¹, R², R³, R⁴, R⁵ and A¹ in the specification are described below.

The term “one or more” may be preferably 1 to 6, and more preferably 1 to 3.

Examples of “lower alkyl” include linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.

Examples of “lower alkylene” include linear or branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene.

Examples of “lower alkenylene” include linear or branched alkenylene groups having 2 to 6 carbon atoms, such as, ethenylene, propenylene, butenylene, pentenylene, and hexenylene.

Examples of “cyclo lower alkyl” include linear or branched cyclo alkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of “lower alkoxy” include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, and 3-methylpentyloxy.

Examples of “halogen” are fluorine, chlorine, bromine, and iodine.

Examples of “lower alkylenedioxy” include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy.

Examples of “lower alkanoyl” include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl.

Examples of “lower alkoxycarbonyl” include (linear or branched alkoxy having 1 to 6 carbon atoms)carbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl.

Examples of “aralkyl group” include groups wherein aryl groups are substituted on the alkyl groups, such as benzyl and phenethyl.

Examples of “aryl group” include monocyclic or polycyclic aryl groups, such as phenyl, tolyl, xylyl, and naphthyl.

Examples of “heterocyclic group” include saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. Examples of preferable heterocyclic groups include the followings (a) to (m) groups:

(a) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;

(b) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, etc.;

(c) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 5 nitrogen atom(s), for example, indolyl, dihydroindolyl (e.g., 2,3-dihydroindolyl, etc.), isoindolyl, indolizinyl, benzimidazolyl, quinolyl, dihydroquinolyl (e.g. 1,4-dihydroquinolyl, etc.), tetrahydroquinolyl (1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, dihydroisoquinolyl (e.g., 3,4-dihydro-1H-isoquinolyl, 1,2-dihydroisoquinolyl, etc.), tetrahydroisoquinolyl (e.g., 1,2,3,4-tetrahydro-1H-isoquinolyl, 5,6,7,8-tetrahydroisoquinolyl, etc.), carbostyril, dihydrocarbostyril (e.g., 3,4-dihydrocarbostyril, etc.), indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-c]pyridyl, etc.,), naphthyridinyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolopyridyl (e.g., pyrazolo[2,3-a]pyridyl, etc.), etc.;

(d) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s), for example, furyl, etc.;

(e) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 oxygen atom(s), for example, benzofuryl, dihydrobenzofuryl (e.g. 2,3-dihydrobenzo[b]furyl, etc.), chromanyl, benzodioxanyl (e.g., 1,4-benzodioxanyl, etc.), dihydrobenzoxazinyl (e.g., 2,3-dihydrobenz-1,4-oxazinyl, etc.), benzodioxolyl (benzo[1,3]dioxolyl, etc.), etc.;

(f) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

(g) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.;

(h) unsaturated condensed 7 to 12-membered heterocyclic groups containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, benzisoxazolyl, furopyridyl (e.g., furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, etc.), etc.;

(i) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), etc.;

(j) saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;

(k) unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, thienyl, etc.;

(l) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 3 sulfur atom(s), for example, benzothienyl (e.g. benzo[b]thienyl, etc.); and

(m) unsaturated condensed 7- to 12-membered heterocyclic groups containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, thienopyridyl (e.g., thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, 4,5-dihydrothieno[3,2-c]pyridyl, thieno[2,3-b]pyridyl, 6,7-dihydrothieno[2,3-b]pyridyl, etc.), imidazothiazolyl (e.g., imidazo[2,1-b]thiazolyl, etc.), dihydroimidazothiazolyl (e.g., 2,3-dihydroimidazo[2,1-b]thiazolyl, etc.), thienopyrazinyl (e.g., thieno[2,3-b]pyrazinyl, etc.), etc.; wherein said heterocyclic groups may be substituted by one or more suitable substituents.

Substituents of “aryl and heterocyclic group, each of which is optionally substituted” represented by R⁵ are each independently one or more substituents selected from the group consisting of:

(1) oxo; (2) lower alkyl optionally substituted with one or more halogens or heterocyclic groups optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; cyano; and oxo; (3) cyclo lower alkyl; (4) lower alkoxy; (5) aryl optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; and cyano; (6) aralkyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; cyano; and oxo; (7) a heterocyclic group optionally substituted with one or more substituents selected from the group consisting of lower alkyl; lower alkoxy; lower alkanoyl; lower alkylsulfonyl; hydroxyl; halogen; carboxy; lower alkoxycarbonyl; amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; lower alkyl thio; cyano; and oxo; (8) hydroxyl; (9) halogen; (10) carboxy; (11) lower alkanoyl; (12) lower alkoxycarbonyl; (13) lower alkylenedioxy; (14) cyano; (15) nitro; (16) sulfo; (17) amino optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkanoyl, and lower alkylsulfonyl; (18) lower alkylsulfonyl; and (19) lower alkyl thio.

The “heterocyclic group” in Item (7) above can be selected from the above-mentioned groups (a) to (m).

Examples of preferable benzodiazepine compounds represented by General Formula (1) include those wherein:

R¹, R², R³, and R⁴ are each independently lower alkyl; A¹ is lower alkylene; and R⁵ is piperidyl, piperazinyl, indolyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydroindolyl, furo[2,3-c]pyridyl, 6,7-dihydrofuro[2,3-c]pyridyl, furo[3,2-c]pyridyl, 4,5-dihydrofuro[3,2-c]pyridyl, furo[2,3-b]pyridyl, 6,7-dihydrofuro[2,3-b]pyridyl, thieno[2,3-c]pyridyl, 6,7-dihydrothieno[2,3-c]pyridyl, 1,2,3,4-tetrahydro-1H-isoquinolyl, carbostyril, 3,4-dihydrocarbostyril, quinolyl, 1,4-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, pyrido[3,4-d]imidazolyl, or pyrido[2,3-d]imidazolyl; each of which is optionally substituted with one or more substituents selected from the group consisting of: (1) oxo; (2a) lower (C₁₋₃) alkyl optionally substituted with 6,7-dihydrofuro[2,3-c]pyridyl or 4,5-dihydrofuro[3,2-c]pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of oxo and lower alkyl; (4a) C₁₋₃ alkoxy; (5a) phenyl; (6a) benzyl; (7a) pyridyl optionally substituted with one or more substituents selected from the group consisting of lower alkyl and lower alkoxy; (9) halogen; (10) carboxy; (12a) C₁₋₃ alkoxycarbonyl; and (13a) C₁₋₄ alkylenedioxy.

The benzodiazepine compound of the present invention represented by Formula (1) or its salt can be readily produced by persons skilled in the art using technical knowledge, based on the Examples and Reference Examples of the present specification. For example, the benzodiazepine compound or its salt can be produced according to the processes shown in the following reaction formulae.

wherein R¹, R², R³, R⁴, R⁵, and A¹ are the same as above, and X¹ is halogen or hydroxyl.

The reaction of the compound of Formula (2) with the compound of Formula (3) wherein X¹ is halogen can be performed in a general inert solvent or without using any solvent in the presence or absence of a basic compound.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower (C₁₋₆) alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixed solvents of such solvents.

The basic compound may be selected from various known compounds. Examples of such compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]nonene-5 (DBN); 1,8-diazabicyclo[5.4.0]undecene-7 (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.

The above reaction may be performed by adding an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.

The compound of Formula (3) is typically used in an amount of at least 0.5 moles, and preferably 0.5 to 10 moles, per mole of the compound of Formula (2).

The basic compound is typically used in an amount of 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (2).

The reaction is typically performed at a temperature of 0° C. to 250° C., and preferably 0° C. to 200° C., and is typically completed in about 1 to about 80 hours.

The reaction of the compound of Formula (2) with the compound of Formula (3) wherein X¹ is hydroxyl is performed in a suitable solvent in the presence of a condensing agent.

Examples of solvents usable herein include water; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve; aprotic polar solvents such as acetonitrile, pyridine, acetone, N,N-dimethyl formamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures of such solvents.

Examples of condensing agents include azocarboxylates such as di-tert-butyl azodicarboxylate, N,N,N′,N′-tetramethyl azodicarboxamide, 1,1′-(azodicarbonyl)dipiperidine, diethyl azodicarboxylate; and phosphorus compounds such as triphenylphosphine and tri-n-butylphosphine.

In this reaction, the compound (3) is typically used in an amount of at least 1 mole, and preferably 1 to 2 moles, per mole of the compound (2).

The condensing agent is typically used in an amount of at least 1 mole, and preferably 1 to 2 moles, per mole of the compound (2).

The reaction proceeds typically at 0 to 200° C., and preferably at about 0 to about 150° C., and is completed in about 1 to about 10 hours.

wherein R¹, R², R³, R⁴, and A¹ are the same as above; R^(5a) is a nitrogen-containing heterocyclic group optionally having substituent(s); and X² is a halogen atom.

Examples of R^(5a) include, among groups represented by the group R⁵ mentioned above, groups obtained by removing hydrogen from saturated or unsaturated, monocyclic or polycyclic, heterocyclic compounds with an N—H bond, the groups optionally having substituent(s).

The reaction of the compound of Formula (4) with the compound of Formula (5) can be performed in a general inert solvent or without using any solvent, in the presence or absence of a basic compound.

Examples of halogen atoms represented by X² include chlorine, bromine, iodine, and like atoms.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethylether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile; and mixtures thereof.

A wide variety of known basic compounds can be used as the basic compound. Examples of such basic compounds include inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; sodium amide; sodium hydride; and potassium hydride; and organic bases, for example, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide; triethylamine; tripropylamine; pyridine; quinoline; 1,5-diazabicyclo[4.3.0]nonene-5 (DBN); 1,8-diazabicyclo[5.4.0]undecene-7 (DBU); and 1,4-diazabicyclo[2.2.2]octane (DABCO). These basic compounds can be used singly or in a combination of two or more.

The above reaction may be performed by adding as a reaction accelerator an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system, as required.

The compound of Formula (5) is typically used in an amount of at least 0.5 moles, and preferably about 0.5 to about 10 moles, per mole of the compound of Formula (4).

The amount of basic compound is typically 0.5 to 10 moles, and preferably 0.5 to 6 moles, per mole of the compound of Formula (4).

The reaction is typically performed at a temperature of 0 to 250° C., and preferably 0 to 200° C., and is typically completed in about 1 to about 80 hours.

wherein R², R³, R⁴, and X² are as defined above; R^(1a) is lower alkyl; R⁷ is lower alkoxy; and R⁶ is lower alkoxycarbonyl.

Examples of lower alkyl groups represented by R^(1a) include alkyl groups with 1 to 6 carbon atoms, such as methyl, ethyl, and propyl groups.

Examples of lower alkoxycarbonyl groups represented by R⁶ include (C₁₋₆ alkoxy)carbonyl groups, such as methoxycarbonyl, and ethoxycarbonyl.

Examples of lower alkoxy groups represented by R⁷ include linear or branched alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, and butoxy.

In the reaction of the compound of Formula (7) with the compound of Formula (8), the compound of Formula (7) is reacted with the carboxylic acid compound of Formula (8) through a general amide bond formation reaction. Conditions for known amide bond formation reactions can be easily employed in the amide formation reaction. For example, the following reaction methods can be employed: (i) a mixed acid anhydride method, in which Carboxylic Acid (8) is reacted with an alkyl halocarboxylate to form a mixed acid anhydride, which is then reacted with Amine (7); (ii) an active ester method, in which Carboxylic Acid (8) is converted to an activated ester such as a phenyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester or the like, or an activated amide with benzoxazoline-2-thione, and the activated ester or amide is reacted with Amine (7); (iii) a carbodiimide method, in which Carboxylic Acid (8) is subjected to a condensation reaction with Amine (7) in the presence of an activating agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), carbonyldiimidazole or the like; and (iv) other methods, for example, a method in which Carboxylic Acid (8) is converted to a carboxylic anhydride using a dehydrating agent such as acetic anhydride, and the carboxylic anhydride is reacted with Amine (7), a method in which an ester of Carboxylic Acid (8) with a lower alcohol is reacted with Amine (7) at a high pressure and a high temperature, and a method in which an acid halide of Carboxylic Acid (8), i.e., a carboxylic acid halide, is reacted with Amine (7).

Generally, the mixed acid anhydride method (i) is performed in a solvent, in the presence or absence of a basic compound. Any solvents used for conventional mixed acid anhydride methods are usable. Specific examples of usable solvents include halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures thereof.

Examples of usable basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic bases, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; potassium hydride; sodium hydride; potassium; sodium; sodium amide; and metal alcoholates such as sodium methylate and sodium ethylate.

Examples of alkyl halocarboxylates usable in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. In this method, Carboxylic Acid (8), an alkyl halocarboxylate, and Amine (7) are preferably used in equimolar amounts, but each of the alkyl halocarboxylate and Carboxylic Acid (8) can also be used in an amount of about 1 to about 1.5 moles per mole of Amine (7).

The reaction is typically performed at about −20 to about 150° C., and preferably at about 10 to about 50° C., typically for about 5 minutes to about 30 hours, and preferably for about 5 minutes to about 25 hours.

Method (iii), in which a condensation reaction is performed in the presence of an activating agent, can be performed in a suitable solvent in the presence or absence of a basic compound. Solvents and basic compounds usable in this method include those mentioned hereinafter as solvents and basic compounds usable in the method in which a carboxylic acid halide is reacted with Amine (7) mentioned above as one of the other methods (iv). A suitable amount of activating agent is typically at least 1 mole, and preferably 1 to 5 moles per mole of Compound (7). When WSC is used as an activating agent, addition of 1-hydroxybenzotriazol to the reaction system allows the reaction to proceed advantageously. The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and is typically completed in about 5 minutes to about 90 hours.

When the method in which a carboxylic acid halide is reacted with Amine (7), mentioned above as one of the other methods (iv), is employed, the reaction is performed in the presence of a basic compound in a suitable solvent. Examples of usable basic compounds include a wide variety of known basic compounds, such as those for use in the method (i) above. In addition to those usable in the mixed acid anhydride method, usable solvents include alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, and methylcellosolve; acetonitrile; pyridine; acetone; and water. The ratio of the carboxylic acid halide to Amine (7) is not limited and can be suitably selected from a wide range. It is typically suitable to use, for example, at least about 1 mole, and preferably about 1 to about 5 moles of the carboxylic acid halide per mole of Amine (7). The reaction is typically performed at about −20 to about 180° C., and preferably at about 0 to about 150° C., and typically completed in about 5 minutes to about 30 hours.

The amide bond formation reaction shown in Reaction Formula 3 above can also be performed by reacting Carboxylic Acid (8) with Amine (7) in the presence of a phosphorus compound serving as a condensing agent, such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, or the like.

The reaction is performed in the presence of a solvent and a basic compound usable for the method in which a carboxylic acid halide is reacted with Amine (7), typically at about −20 to about 150° C., and preferably at about 0 to about 100° C., and is typically completed in about 5 minutes to about 30 hours. It is suitable to use each of the condensing agent and Carboxylic Acid (8) in amounts of at least about 1 mole, and preferably about 1 to about 2 moles, per mole of Amine (7).

The reaction converting the compound of Formula (9) to the compound of Formula (10) can be performed by, for example, [1] reducing the compound of Formula (9) in a suitable solvent using a catalytic hydrogenation reducing agent, or [2] reducing the compound of Formula (9) in a suitable inert solvent using as a reducing agent such as a mixture of an acid with a metal or metal salt, a mixture of a metal or metal salt with an alkali metal hydroxide, sulfide, or ammonium salt.

When Method [1] in which a catalytic hydrogenation reducing agent is used, examples of usable solvents are water; acetic acid; alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and diethylene glycol dimethyl ether; esters such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide; and mixtures thereof. Examples of usable catalytic hydrogenation reducing agents include palladium, palladium black, palladium carbon, platinum carbon, platinum, platinum black, platinum oxide, copper chromite, and Raney nickel. The reducing agent is typically used in an amount of about 0.02 times to about equal to the weight of the compound of Formula (9). The reaction temperature is typically about −20 to about 150° C., and preferably about 0 to about 100° C. The hydrogen pressure is typically about 1 to 10 atm. The reaction is typically completed in about 0.5 to about 100 hours. An acid such as hydrochloric acid may be added to the reaction.

When Method [2] above is used, a mixture of iron, zinc, tin, or tin (II) chloride with a mineral acid such as hydrochloric acid or sulfuric acid; or a mixture of iron, iron (II) sulfate, zinc, or tin with an alkali metal hydroxide such as sodium hydroxide, a sulfide such as ammonium sulfide, aqueous ammonia solution, or an ammonium salt such as ammonium chloride or the like, can be used as a reducing agent. Examples of inert solvents are water; acetic acid; alcohols such as methanol and ethanol; ethers such as dioxane; and mixtures thereof. Conditions for the reduction reaction can be suitably selected according to the reducing agent to be used. For example, when a mixture of tin (II) chloride and hydrochloric acid is used as a reducing agent, the reaction is advantageously performed at about 0 to about 150° C. for about 0.5 to about 10 hours. A reducing agent is used in an amount of at least 1 mole, and preferably about 1 to 5 moles, per mole of the compound of Formula (9).

The reaction converting the compound of Formula (10) to the compound of Formula (6b) is performed under the same reaction conditions as those for the reaction of the compound of Formula (7) with the compound of Formula (8).

The reaction of the compound of Formula (6b) with the compound of Formula (11) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) and the compound of Formula (3) shown in Reaction Formula 1 above.

wherein R¹, R², R³, R⁴, and R⁷ are the same as above.

The reaction of the compound of Formula (12) with the compound of Formula (13) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (7) with the compound of Formula (8) shown in Reaction Formula 3 above.

wherein R¹, R², R³, R⁴, R⁷, A¹, and X² are the same as above; and X³ is a halogen atom.

The reaction converting the compound of Formula (6) to the compound of Formula (2) can be performed in a suitable solvent in the presence of an acid.

Examples of solvents include water; lower (C₁₋₆) alcohols such as methanol, ethanol, and isopropanol; ethers such as dioxane, tetrahydrofuran, and diethylether; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; polar solvents such as acetonitrile; and mixtures thereof. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; aliphatic acids such as formic acid and acetic acid; sulfonic acids such as p-toluenesulfonic acid; Lewis acids such as boron fluoride, aluminium chloride, and boron tribromide; iodides such as sodium iodide and potassium iodide; and mixtures of these iodides and Lewis acids.

The reaction is performed typically at about 0 to about 200° C., and preferably at about 0 to about 150° C., and is typically completed in about 0.5 to about 25 hours. The amount of acid is typically about 1 to about 10 moles, and preferably about 1 to about 2 moles, per mole of the compound of Formula (6).

Examples of halogen atoms represented by X³ include chlorine, bromine, iodine, and like atoms. The halogen atom represented by X³ is preferably one having an atomic number equal to or higher than that of the halogen atom represented by X².

The reaction of the compound of Formula (2) with the compound of Formula (14) can be performed under the same reaction conditions as those for the reaction of the compound of Formula (2) with the compound of Formula (3) shown in Reaction Formula 1 above, wherein X¹ is a halogen atom.

The compound of Formula (1) according to the present invention and the starting materials thereof can be produced using a known or conventional synthetic method other than the production method described above.

In addition, compounds in the form in which a solvate (for example, a hydrate, ethanolate, etc.) was added to the starting material compounds and object compounds shown in each of the reaction formulae are included in each of the formulae.

The compound of Formula (1) according to the present invention includes stereoisomers and optical isomers.

The starting material compounds and object compounds represented by each of the reaction formulae can be used in a suitable salt form.

Each of the object compounds obtained according to the above reaction formulae can be isolated and purified from the reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a general purification procedure such as column chromatography, recrystallization, etc.

Among the compounds of the present invention, those having a basic group or groups can easily form salts with common pharmaceutically acceptable acids. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids, methansulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.

Among the compounds of the present invention, those having an acidic group or groups can easily form salts by reacting with pharmaceutically acceptable basic compounds. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.

In the compound of the present invention, one or more atoms can be substituted with one or more isotopic atoms. Examples of the isotopic atoms include deuterium (²H), tritium (³H), ¹³C, ¹⁴N, ¹⁸O, etc.

The following is an explanation of pharmaceutical preparations comprising the compound of the present invention as an active ingredient.

Such pharmaceutical preparations are obtained by formulating the compound of the present invention into general pharmaceutical preparations, using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.

The form of such pharmaceutical preparations can be selected from various forms according to the purpose of therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.

To form tablets, any of various known carriers can be used, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, aliphatic acid esters of polyoxyethylenesorbitan, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and other disintegrants; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc.

Such tablets may be coated with general coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.

To form pills, any of various known carriers can be used, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; laminaran, agar and other disintegrants; etc.

To form suppositories, any of various known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, etc.

To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic with blood. Any of various known widely used diluents can be employed to prepare the solution, emulsion or suspension. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, aliphatic acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution, and may contain general solubilizers, buffers, analgesic agents, etc., and further, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.

The proportion of the compound of the present invention in the pharmaceutical preparation is not limited and can be suitably selected from a wide range. It is typically preferable that the pharmaceutical preparation contain the compound of the present invention in a proportion of 1 to 70 wt. %.

The route of administration of the pharmaceutical preparation according to the present invention is not limited, and the preparation can be administered by a route suitable for the form of the preparation, the patient's age and sex, the conditions of the disease, and other conditions.

For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with general injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.

The dosage of the pharmaceutical preparation is suitably selected according to the method of use, the patient's age and sex, the severity of the disease, and other conditions, and is typically about 0.001 to about 100 mg/kg body weight/day, and preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.

Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage larger than the above range may be required.

When administered to the human body as a pharmaceutical, the compound of the present invention may be used concurrently with, or before or after, antithrombotics such as blood clotting inhibitors and antiplatelet agents (e.g., warfarin, aspirin, etc.). Further, the present compound may be used concurrently with, or before or after, drugs for treating chronic diseases, such as antihypertensive drugs (ACE inhibitors, beta blockers, angiotensin II receptor antagonists), heart failure drugs (cardiotonic agents, diuretics), and diabetes treatment agents.

The compound of the present invention has potent blocking effects on human Kv1.5 and/or GIRK1/4 channels, and weak blocking effects on HERG channels. Thus, the compound of the invention has characteristics as an atrial-selective K⁺ channel-blocking agent.

Therefore, the compound of the invention can be used as a pharmacologically active substance that is safer and provides a more potent effect on the prolongation of the atrial refractory period than conventional antiarrhythmic agents. The compound of the invention is preferably used as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (elimination of arrhythmia and/or prevention of the occurrence of arrhythmia). The compound of the invention is particularly preferably used as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm). The compound of the invention can also be used as a prophylactic agent for thromboembolism such as cerebral infarction and as a therapeutic agent for heart failure.

The compound having potent blocking effects on both human Kv1.5 and human GIRK1/4 channels has more potent atrial refractory period prolongation effects and is highly safe, compared to compounds inhibiting either one of the channels. Furthermore, this compound has greater therapeutic effects on atrial fibrillation (defibrillation and maintenance of sinus rhythm) than compounds inhibiting either one of the channels. Therefore, the compound having potent blocking effects on both the human Kv1.5 and human GIRK1/4 channels is particularly useful as a therapeutic agent for arrhythmia such as atrial fibrillation, atrial flutter, and atrial tachycardia (termination of arrhythmia and/or prevention of the occurrence of arrhythmia). This compound is particularly useful as a therapeutic agent for atrial fibrillation (defibrillation and maintenance of sinus rhythm).

DESCRIPTION OF EMBODIMENTS

The following Examples are intended to illustrate the present invention in further detail.

1. First Invention Reference Example 1 Synthesis of 8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium ethoxide (204 mg) was added to an ethanol solution (15 ml) of N-(2-amino-5-methoxyphenyl)-N-methylmalonamic acid ethyl ester (266 mg). The mixture was stirred at 65° C. for 2.5 hours. The reaction liquid was cooled to room temperature, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (176.3 mg) as a white powder.

¹H-NMR (CDCl₃) δppm: 3.36 (2H, s), 3.43 (3H, s), 3.84 (3H, s), 6.79-6.83 (1H, m), 7.06-7.09 (1H, m), and 8.72 (1H, br-s).

Reference Example 2 Synthesis of 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 44 mg) was suspended in of DMF (8 ml), and was cooled to 0° C. in an ice water bath. 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Ethyl iodide (187 mg) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1). The purified product was condensed to dryness to give the title compound (190.2 mg) as a yellow solid.

¹H-NMR (CDCl₃) δppm: 1.11 (3H, t, J=7.1 Hz), 3.32 (2H, m), 3.59-3.68 (1H, m), 3.85 (3H, s), 4.18-4.30 (1H, m), 6.78 (1H, d, J=2.8 Hz), 6.84 (1H, dd, J=9.0 and 2.8 Hz), 7.26 (1H, d, J=9.0 Hz).

Reference Example 3 Synthesis of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 76 mg) was suspended in of DMF (8 ml). 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (190 mg) was added thereto at 0° C. The mixture was stirred at the same temperature for an hour. Methyl iodide (0.19 ml) was added thereto, and the mixture was stirred at room temperature for three days. Water was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed to dryness to give the title compound (169 mg) as yellow powder.

¹H-NMR (CDCl₃) δppm: 0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.65-3.76 (1H, m), 3.85 (3H, s), 4.12-4.24 (1H, m), 6.73 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), and 7.22 (1H, d, J=9.0 Hz).

Reference Example 4 Synthesis of 7-methoxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 128 mg) was suspended in of DMF (10 ml). 8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (176 mg) was added thereto at 0° C. The mixture was stirred at the same temperature for an hour. Methyl iodide (0.25 mg) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and condensed under reduced pressure. The residue was recrystallized from hexane to give the title compound (161.6 mg) as a white powder.

¹H-NMR (CDCl₃) δppm: 0.87 (3H, s), 1.54 (3H, s), 3.40 (3H, s), 3.42 (3H, s), 3.84 (3H, s), 6.73 (1H, s), 6.84 (1H, d, J=8.9 Hz), 7.14 (1H, d, J=8.9 Hz).

Reference Example 5 Synthesis of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1.0M-boron tribromide/dichloromethane solution (1.22 ml) was added to a dichloromethane solution (3 ml) of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (169 mg) at 0° C. The mixture was stirred at room temperature overnight. Water and methanol were added to the reaction mixture, and extraction was performed using a dichloromethane/methanol mixture (dichloromethane:methanol=10:1). The organic layer was dried over anhydrous sodium sulfate, and condensed to dryness under reduced pressure to give the title compound (156.4 mg) as a white powder.

¹H-NMR (CDCl₃) δppm: 0.90 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.55 (3H, s), 3.41 (3H, s), 3.66-3.78 (1H, m), 4.12-4.23 (1H, m), 6.79 (1H, d, J=2.7 Hz), 6.84 (1H, dd, J=8.8 and 2.7 Hz), 6.88 (1H, s), 7.18 (1H, d, J=8.8 Hz).

Reference Example 6 Synthesis of 7-hydroxy-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Reference Example 5 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.90 (3H, s), 1.49 (3H, s), 3.39 (3H, s), 3.40 (3H, s), 6.73 (1H, d, J=2.7 Hz), 6.80 (1H, dd, J=8.9 and 2.7 Hz), 7.13 (1H, d, J=8.9 Hz).

Reference Example 7 Synthesis of trifluoromethanesulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester

A dichloromethane solution (50 ml) of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.6 g) was cooled with ice. After adding of triethylamine (1.5 ml) to the solution, trifluoromethane sulfonic anhydride (1.9 ml) was added, and the mixture was stirred at room temperature for 4 hours. Triethylamine (0.75 ml) and trifluoromethane sulfonic anhydride (0.75 ml) were further added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→5:5). The purified product was condensed to dryness under reduced pressure to give the title compound (3.4 g) as a white solid (yield=86%).

¹H-NMR (CDCl₃) δppm: 0.87 (3H, s), 1.23 (3H, t, J=7.2 Hz), 1.52 (3H, s), 3.42 (3H, s), 3.81-3.91 (1H, m), 4.04-4.14 (1H, m), 7.15-7.22 (2H, m), 7.40 (1H, d, J=8.9 Hz).

Reference Example 8 Synthesis of trifluoromethanesulfonic acid 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester

The synthesis of the title compound was performed in the same manner as in Reference Example 7 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 3.29 (1H, d, J=12.7 Hz), 3.43 (6H, s), 3.48 (1H, d, J=12.7 Hz), 7.21-7.26 (2H, m), 7.38-7.41 (1H, m).

Reference Example 9 Synthesis of trifluoromethanesulfonic acid 1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester

The synthesis of the title compound was performed in the same manner as in Reference Example 7 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.88 (3H, s), 1.56 (3H, s), 3.44 (3H, s), 3.45 (3H, s), 7.16-7.21 (2H, m), 7.33 (1H, d, J=8.9 Hz).

Reference Example 10 Synthesis of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

Trifluoromethanesulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.12 g), zinc cyanide (70 mg), tris (dibenzylideneacetone) dipalladium (7 mg), 1,1′-bis (diphenylphosphino) ferrocene (8 mg), and zinc powder (2 mg) were added to DMF (1 ml), and the mixture was heated for 20 minutes at 170° C. (microwave reactor). The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→0:100). The purified product was condensed under reduced pressure to give the title compound (77 mg) as a white solid.

¹H-NMR (CDCl₃) δppm: 0.88 (3H, s), 1.25 (3H, t, J=7.1 Hz), 1.55 (3H, s), 3.44 (3H, s), 3.89-3.95 (1H, m), 4.05-4.11 (1H, m), 7.43 (1H, d, J=9.1 Hz), 7.53-7.56 (2H, m).

Reference Example 11 Synthesis of 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 3.25 (1H, d, J=12.7 Hz), 3.438 (3H, s), 3.444 (3H, s), 3.50 (1H, d, J=12.7 Hz), 7.42 (1H, J=8.4 Hz), 7.57-7.62 (2H, m).

Reference Example 12 Synthesis of 1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.88 (3H, s), 1.56 (3H, s), 3.45 (3H, s), 3.46 (3H, s), 7.34-7.37 (1H, m), 7.53-7.57 (2H, m).

Reference Example 13 Synthesis of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.0 g) and Raney nickel (3.0 g) were suspended in formic acid (10 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→20:80). The purified product was condensed under reduced pressure to give the title compound (0.92 g) as a yellowish-white solid (yield=92%).

¹H-NMR (CDCl₃) δppm: 0.88 (3H, s), 1.26 (3H, t, J=7.1 Hz), 1.56 (3H, s), 3.48 (3H, s), 3.92-3.99 (1H, m), 4.07-4.15 (1H, m), 7.50 (1H, d, J=8.9 Hz), 7.77-7.80 (2H, m), 10.01 (1H, s).

Reference Example 14 Synthesis of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)but-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.59 g), 2-(but-3-ynyl)isoindol-1,3-dione (0.3 g), dichlorobis(triphenyl phosphine)palladium (II)(53 mg), copper(I) iodide (29 mg), and triethylamine (0.39 ml) were added to DMF (4 ml). The mixture was heated at 150° C. (microwave reactor) for 10 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40→30:70). The purified product was condensed under reduced pressure to give the title compound (0.51 g) as a yellowish-white solid.

¹H-NMR (CDCl₃) δppm: 0.84 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.84 (2H, t, J=6.3 Hz), 3.38 (3H, s), 3.68-3.80 (1H, m), 3.99 (2H, t, J=6.3 Hz), 4.00-4.15 (1H, m), 7.19-7.20 (3H, m), 7.73-7.76 (2H, m), 7.87-7.89 (2H, m).

Reference Example 15 Synthesis of 7-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-prop-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Reference Example 14 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.83 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 3.38 (3H, s), 3.71-3.89 (1H, m), 4.03-4.18 (1H, m) 4.70 (2H, s), 7.20-7.31 (3H, m), 7.75-7.78 (2H, m), 7.90-7.93 (2H, m).

Reference Example 16 Synthesis of (E)-3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)acrylic acid ethyl ester

Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester (0.40 g), ethyl acrylate (0.13 g), dichlorobis (triphenylphosphine) palladium (II)(35 mg), lithium chloride (64 mg), and triethylamine (0.19 ml) were added to DMF (4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70). The purified product was condensed under reduced pressure to give the title compound (0.36 g) as a pale yellow solid.

¹H-NMR (CDCl₃) δppm: 0.88 (3H, s), 1.22 (3H, t, J=7.2 Hz), 1.35 (3H, t, J=7.1 Hz), 1.55 (3H, s), 3.44 (3H, s), 3.81-3.90 (1H, m), 4.08-4.25 (1H, m), 4.13 (2H, q, J=7.1 Hz), 6.45 (1H, d, J=16.0 Hz), 7.25-7.27 (1H, m), 7.32-7.37 (2H, m), 7.65 (1H, d, J=16.0 Hz).

Reference Example 17 Synthesis of 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid ethyl ester

10% Palladium on carbon (0.1 g) was added to a methanol solution (10 ml) of (E)-3-(1-ethyl 3,3,5-trimethyl 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)acrylic acid ethyl ester (0.36 g). The mixture was subjected to catalytic reduction at room temperature and under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound (0.29 g) as a brown solid.

¹H-NMR (CDCl₃) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.2 Hz), 1.23 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.65 (2H, t, J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz), 3.40 (3H, s), 3.77-3.90 (1H, m), 4.01-4.21 (3H, m), 7.07-7.11 (2H, m), 7.21-7.26 (1H, m).

Reference Example 18 Synthesis of 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid

50% Sodium hydroxide aqueous solution (1 ml) was added to a methanol (20 ml) solution of 3-(1-ethyl 3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl) propionic acid ethyl ester (1.1 g). The mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by washing with ether. A hydrochloric acid was added to the aqueous layer, followed by extraction using ethyl acetate and drying using magnesium sulfate. The dried product was condensed under reduced pressure to give the title compound (0.97 g) as a colorless oily matter.

¹H-NMR (CDCl₃) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.2 Hz), 1.52 (3H, s), 2.72 (2H, t, J=7.5 Hz), 3.00 (2H, t, J=7.5 Hz), 3.40 (3H, s), 3.72-3.88 (1H, m), 4.03-4.21 (1H, m), 7.09-7.13 (2H, m), 7.23-7.26 (1H, m).

Reference Example 19 Synthesis of 2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl carbamic acid tert-butyl ester

Diphenylphosphoryl azide (1.0 ml) and tert-butanol (10 ml) were added to a THF solution (10 ml) of 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid (0.97 g) and triethylamine (0.67 ml). The mixture was stirred at 100° C. overnight. The reaction liquid was cooled to room temperature, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50). The purified product was condensed under reduced pressure to give the title compound (0.38 g) as a colorless oily matter.

¹H-NMR (CDCl₃) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.2 Hz), 1.43 (9H, s), 1.53 (3H, s), 2.83 (2H, t, J=7.1 Hz), 3.38 (2H, t, J=7.1 Hz), 3.41 (3H, s), 3.71-3.85 (1H, m), 4.03-4.19 (1H, m), 4.57 (1H, br), 7.06-7.11 (2H, m), 7.22-7.27 (1H, m).

Reference Example 20 Synthesis of 5-(2,2-dihydroxyethyl)-5H-furo[3,2-c]pyridin-4-one

Sodium hydride (60% in oil, 0.36 g) was suspended in DMF (10 ml), and was cooled to 0° C. in an ice water bath. 5H-Furo[3,2-c]pyridin-4-one (1.0 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde diethylacetal (2.6 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochrolic acid (5.8 ml) was added to an acetone solution (20 ml) of the residue, and the liquid was stirred at 60° C. for 5 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.90 g) as a white solid.

¹H-NMR (DMSO-d₆) δppm: 3.88 (d, J=5.4 Hz, 2H), 4.95-5.03 (m, 1H), 6.08 (d, J=6.4 Hz, 2H), 6.69 (dd, J=7.4, 0.8 Hz, 1H), 6.94 (dd, J=2.1 and 0.8 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H).

Reference Example 21 Synthesis of 5-(2,2-dihydroxy-ethyl)-7-methyl-5H-furo[3,2-c]pyridin-4-one

The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.28 (3H, d, J=1.0 Hz), 3.85 (2H, d, J=5.4 Hz), 4.95-5.02 (1H, m), 6.06 (2H, d, J=6.3 Hz), 6.95 (1H, d, J=2.1 Hz), 7.33 (1H, d, J=1.0 Hz), 7.90 (1H, d, J=2.1 Hz).

Reference Example 22 Synthesis of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one

The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 2.36 (s, 3H), 3.86 (d, J=5.4 Hz, 2H), 4.94-4.98 (m, 1H), 6.04 (d, J=6.4 Hz, 2H), 6.52 (s, 1H), 6.59 (d, J=7.4 Hz, 1H), 7.41 (d, J=7.4 H, 1H).

Reference Example 23 Synthesis of 5-(2,2-dihydroxyethyl)-2,3-dimethyl-5H-furo[3,2-c]pyridin-4-one

The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 2.18 (3H, s), 2.28 (3H, s), 3.84 (2H, d, J=5.4 Hz), 4.95-5.02 (1H, m), 6.04 (2H, d, J=6.2 Hz), 6.53 (1H, d, J=7.4 Hz), 7.38 (1H, d, J=7.4 Hz).

Reference Example 24 Synthesis of 5-(2,2-dihydroxyethyl)-2,7-dimethyl-5H-furo[3,2-c]pyridin-4-one

The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 2.14 (3H, s), 2.39 (3H, s), 3.82 (2H, d, J=5.4 Hz), 4.95-5.01 (1H, m), 6.10 (2H, d, J=6.2 Hz), 6.55 (1H, s), 7.24 (1H, s).

Reference Example 25 Synthesis of 6-(2,2-dihydroxyethyl)-4-methyl-6H-furo[2,3-c]pyridin-7-one

The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 2.17 (3H, s), 3.86 (2H, d, J=5.4 Hz), 4.95-5.01 (1H, m), 6.06 (2H, d, J=6.2 Hz), 6.92 (1H, d, J=1.8 Hz), 7.17 (1H, s), 8.10 (1H, d, J=1.8 Hz).

Reference Example 26 Synthesis of 5-(2,2-dihydroxyethyl)-5H-thieno[3,2-c]pyridin-4-one

The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 3.90 (d, J=6.3 Hz, 2H), 4.99-5.04 (m, 1H), 6.07 (d, J=6.3 Hz, 2H), 6.86 (d, J=7.2 Hz, 1H), 7.41-7.49 (m, 2H), 7.57-7.64 (m, 1H).

Reference Example 27 Synthesis of 6-(2,2-dihydroxyethyl)-6H-thieno[2,3-c]pyridin-7-one

The synthesis of the title compound was performed in the same manner as in Reference Example 20 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 3.98 (d, J=5.3 Hz, 2H), 5.11-5.16 (m, 1H), 6.04 (d, J=6.4 Hz, 1H), 6.66 (d, J=7.1 Hz, 2H), 7.27 (d, J=5.2 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.84 (d, J=5.2H, 1H).

Reference Example 28 (1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-acetonitrile

To a solution of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.11 g) in DMF (15 ml) was added sodium cyanide (0.59 g) at room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.84 g) as a pale yellow oil.

¹H NMR (CDCl₃), δppm: 0.85 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.54 (3H, s), 3.43 (3H, s), 3.77-3.86 (3H, m), 4.09-4.19 (1H, m), 7.21-7.24 (2H, m), 7.34 (1H, d, J=8.3 Hz).

Reference Example 29 2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-2-methyl-propionitrile

(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-acetonitrile (0.84 g) was dissolved in DMF (20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 0.259 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.405 ml) was added thereto, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction mixture, and the mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.9 g) as a white powder.

¹H NMR (CDCl₃), δppm: 0.84 (3H, s), 1.20 (3H, t, J=7.06 Hz), 1.54 (3H, s), 1.77 (6H, s), 3.45 (3H, s), 3.78-3.87 (1H, m), 4.09-4.18 (1H, m), 7.34 (3H, s).

Reference Example 30 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carboxylic acid

To a t-butanol (20 ml) and H2O (5 ml) solution of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.25 g) and 2-methyl-2-butene (3.25 ml) were added sodium dihydrogenphosphate (0.92 g) and sodium chlorite (2.081 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure to give the title compound (0.98 g) as a white powder.

mp: 296-299° C.

Reference Example 31 7-Bromomethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

Lithium bromide (0.678 g) was added to an THF solution (2.3 ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.24 g) as a white solid.

¹H NMR (CDCl₃), δppm: 0.85 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.43 (3H, s), 3.77-3.87 (1H, m), 4.08-4.17 (1H, m), 4.49 (2H, s), 7.28-7.29 (3H, m).

Reference Example 32 1-Ethyl-7-(3-hydroxy-propyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid (1.0 g) was dissolved in THF (20 ml) and was cooled to 0° C. in ice water bath. Triethylamine (0.525 ml) and ethyl chloroformate (0.325 ml) were added to this solution and stirred for 30 minutes at same temperature. Sodium borohydride (0.36 g) was added to the mixture under cooling in ice methanol bath. Methanol (0.64 ml) was added dropwise to the mixture and stirred for 1 hour at same temperature. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.71 g) as a colorless oil.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.88-1.95 (2H, m), 2.76 (2H, t, J=7.8 Hz), 3.41 (3H, s), 3.71 (2H, t, J=6.3 Hz), 3.74-3.83 (1H, m), 4.10-4.19 (1H, m), 7.07 (1H, d, J=1.8 Hz), 7.11 (1H, dd, J=8.3 and 1.8 Hz), 7.23 (1H, d, J=8.3 Hz)

Reference Example 33 1-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 184-185° C.

Reference Example 34 1-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 204-205° C.

Reference Example 35 1-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 163-166° C.

Reference Example 36 1-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 154-155° C.

Reference Example 37 1-Cyclopropyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.43 (2H, br), 1.07 (2H, br), 1.66 (3H, br), 3.17-3.23 (1H, m), 7.35 (1H, br), 7.50-7.56 (2H, m), 8.67 (1H, br).

Reference Example 38 1-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.22-0.23 (2H, m), 0.46-0.48 (2H, m), 0.98-1.07 (1H, m), 3.90 (1H, br-d), 7.38-7.54 (3H, m), 9.42 (1H, br).

Reference Example 39 1-Cyclopropyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.44 (2H, br), 1.08 (2H, br), 1.30 (6H, br), 3.20-3.25 (1H, m), 7.49 (1H, d, J=1.8 Hz), 7.58 (1H, d, J=8.4 Hz), 7.78 (1H, dd, J=8.4, 1.8 Hz), 9.98 (1H, s).

Reference Example 40 1-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 124-125° C.

Reference Example 41 1-Cyclopropyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

1-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.0 g) was dissolved in DMF (10 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 0.167 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.261 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water (100 ml) was added to the reaction mixture, and was cooled to 0° C. in ice water bath. The precipitated insoluble matter was separated and dried to give the title compound (0.61 g) as a white powder.

¹H NMR (CDCl₃), δppm: 0.10-0.17 (1H, m), 0.66-0.73 (1H, m), 0.82-0.92 (1H, m), 0.89 (3H, s), 1.21-1.29 (1H, m), 1.55 (3H, s), 3.16-3.22 (1H, m), 3.41 (3H, s), 7.50-7.57 (3H, m).

Reference Example 42 1-Isobutyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.72 (3H, d, J=6.7 Hz), 0.75 (3H, d, J=6.7 Hz), 0.86 (3H, s), 1.55 (3H, s), 1.77-1.88 (1H, m), 3.35 (1H, dd, J=13.7, 6.6 Hz), 3.45 (3H, s), 4.40 (1H, dd, J=13.7, 8.4 Hz), 7.41 (1H, d, J=8.4 Hz), 7.53-7.57 (2H, m).

Reference Example 43 1-(2-Methoxy-ethyl)-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.89 (3H, s), 1.55 (3H, s), 3.32 (3H, s), 3.43 (3H, s), 3.59 (1H, ddd, J=10.4, 5.0, 3.7 Hz), 3.75 (1H, ddd, J=10.4, 7.8, 3.4 Hz), 3.94 (1H, ddd, J=14.4, 7.8, 3.7 Hz), 4.12 (1H, ddd, J=14.4, 5.0, 3.4 Hz), 7.52-7.55 (2H, m), 7.81-7.84 (1H, m).

Reference Example 44 5-Cyclopropyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 252-253° C.

Reference Example 45 5-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 219-220° C.

Reference Example 46 5-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 234-236° C.

Reference Example 47 5-(2-Methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 247-248° C.

Reference Example 48 Methanesulfonic acid 3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl ester

The synthesis of the title compound was obtained from 1-ethyl-7-(3-hydroxypropyl)-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine and methanesulfonyl chloride in a conventional matter.

¹H NMR (CDCl₃), δppm: 0.86 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.05-2.16 (2H, m), 2.79 (2H, t, J=7.6 Hz), 3.03 (3H, s), 3.42 (3H, s), 3.74-3.83 (1H, m), 4.10-4.18 (1H, m), 4.26 (2H, t, J=6.2 Hz), 7.07 (1H, dd, J=8.3 and 2.0 Hz), 7.10 (1H, d, J=2.0 Hz), 7.25 (1H, d, J=8.3 Hz).

Reference Example 49 1-Cyclopropyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.10-0.20 (1H, m), 0.66-0.73 (1H, m), 0.73-0.94 (1H, m), 0.89 (3H, s), 1.21-1.28 (1H, m), 1.55 (3H, s), 3.91-3.45 (1H, m), 3.45 (3H, s), 7.57 (1H, d, 8.4 Hz), 7.74 (1H, d, J=1.8 Hz), 7.79 (1H, dd, J=8.4, 1.8 Hz), 10.01 (1H, s).

Reference Example 50 1-Isobutyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.71 (3H, d, J=6.7 Hz), 0.75 (3H, d, J=6.7 Hz), 0.86 (3H, s), 1.53 (3H, s), 1.76-1.90 (1H, m), 3.39 (1H, dd, J=13.6, 6.6 Hz), 3.49 (3H, s), 4.42 (1H, dd, J=13.6, 8.4 Hz), 7.47 (1H, d, J=9.0 Hz), 7.76-7.79 (2H, m), 10.01 (1H, s).

Reference Example 51 1-(2-Methoxy-ethyl)-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.88 (3H, s), 1.55 (3H, s), 3.31 (3H, s), 3.48 (3H, s), 3.60 (1H, ddd, J=10.4, 5.2, 4.1 Hz), 3.74 (1H, ddd, J=10.4, 7.1, 4.1 Hz), 4.01-4.15 (2H, m), 7.75-7.78 (2H, m), 7.80-7.83 (1H, m), 10.01 (1H, s).

Reference Example 52 5-Isobutyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 208-211° C.

Reference Example 53 5-Cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 183-188° C.

Reference Example 54 1,3,3-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaz epine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 289-294° C.

Reference Example 55 1-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 215-218° C.

Reference Example 56 3,3,5-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 250-251° C.

Reference Example 57 5-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 10 using appropriate starting materials.

mp: 241-247° C.

Reference Example 58 1,3,3-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 208-210° C.

Reference Example 59 1-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.07 (3H, br), 1.29 (3H, t, J=7.1 Hz), 1.57 (3H, br), 4.57 (2H, q, J=7.1 Hz), 7.50 (1H, d, J=8.5 Hz), 7.57 (1H, br), 7.77 (1H, dd, J=8.5, 1.8 Hz), 8.42 (1H, br). 9.99 (1H, s).

Reference Example 60 3,3,5-Trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 197-202° C.

Reference Example 61 5-Ethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

mp: 188-191° C.

Reference Example 62 5-Cyclopropylmethyl-1-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.15-0.24 (2H, m), 0.38-0.51 (2H, m), 0.87 (3H, s), 0.93-1.01 (1H, m), 1.55 (3H, s), 3.32 (3H, s), 3.53-3.62 (1H, m), 3.73-3.79 (1H, m), 3.97-4.04 (1H, m), 4.06-4.13 (1H, m), 7.55 (1H, dd, J=8.5, 1.9 Hz), 7.66 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=8.5 Hz).

Reference Example 63 1-Cyclopropylmethyl-5-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.14-0.22 (2H, m), 0.38-0.49 (2H, m), 0.87 (3H, s), 0.93-1.02 (1H, m), 1.55 (3H, s), 3.34 (3H, s), 3.53-3.65 (1H, m), 3.77-3.83 (1H, m), 3.91-3.98 (1H, m), 4.05-4.13 (1H, m), 7.45 (1H, d, J=8.5 Hz), 7.53 (1H, dd, J=8.5, 1.9 Hz), 8.10 (1H, d, J=1.9 Hz).

Reference Example 64 5-Cyclopropyl-1-cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile

The synthesis of the title compound was performed in the same manner as in Reference Example 41 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.03-0.19 (3H, m), 0.27-0.41 (2H, m), 0.61-0.68 (1H, m), 0.81-0.93 (1H, m), 0.88 (3H, s), 1.21-1.29 (2H, m), 1.54 (3H, s), 3.06-3.26 (1H, m), 3.42 (1H, dd, J=14.3, 6.8 Hz), 4.31 (1H, dd, J=14.3, 7.5 Hz), 7.38 (1H, d, J=8.5. Hz), 7.53 (1H, dd, J=8.5, 1.8 Hz), 7.72 (1H, d, J=1.8 Hz).

Reference Example 65 5-Cyclopropylmethyl-1-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.13-0.25 (2H, m), 0.37-0.48 (2H, m), 0.87 (3H, s), 0.96-1.03 (1H, m), 1.55 (3H, s), 3.32 (3H, s), 3.54-3.59 (1H, m), 3.66 (1H, dd, J=14.2, 6.4 Hz), 3.75 (1H, ddd, J=10.3, 7.2, 4.7 Hz), 4.04-4.19 (3H, m), 7.78 (1H, dd, J=8.4, 1.7 Hz), 7.82 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=1.7 Hz), 10.0 (1H, s).

Reference Example 66 1-Cyclopropylmethyl-5-(2-methoxy-ethyl)-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.14-0.24 (2H, m), 0.38-0.50 (2H, m), 0.87 (3H, s), 0.97-1.07 (1H, m), 1.55 (3H, s), 3.33 (3H, s), 3.53-3.59 (1H, m), 3.65 (1H, dd, J=14.2, 6.4 Hz), 3.73-3.79 (1H, m), 4.03-4.16 (3H, m), 7.51 (1H, d, J=8.4 Hz), 7.79 (1H, dd, J=8.4, 1.9 Hz), 8.19 (1H, d, J=1.9 Hz), 10.0 (1H, s).

Reference Example 67 5-Cyclopropyl-1-cyclopropylmethyl-3,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde

The synthesis of the title compound was performed in the same manner as in Reference Example 13 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.09-0.07 (1H, m), 0.09-0.20 (2H, m), 0.27-0.40 (2H, m), 0.62-0.68 (1H, m), 0.83-0.92 (1H, m), 0.88 (3H, s), 1.20-1.28 (2H, m), 1.54 (3H, s), 3.27-3.33 (1H, m), 3.45 (1H, dd, J=14.3, 6.8 Hz), 4.34 (1H, dd, J=14.3, 7.5 Hz), 7.43 (1H, d, J=8.4 Hz), 7.77 (1H, dd, J=8.4, 1.9 Hz), 7.92 (1H, d, J=1.9 Hz), 10.0 (1H, s).

Example 1 Synthesis of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

10% Palladium on carbon (0.52 g) was added to a methanol solution (50 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl) but-1-ynyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.2 g). The mixture was subjected to catalytic reduction at room temperature under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound (1.93 g) as a brown solid.

¹H-NMR (CDCl₃) δppm: 0.81 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.61-1.79 (4H, m), 2.68 (2H, t, J=7.0 Hz), 3.40 (3H, s), 3.71-3.81 (3H, m), 4.01-4.18 (1H, m), 7.02-7.08 (2H, m), 7.20 (1H, d, J=8.3 Hz), 7.70-7.74 (2H, m), 7.83-7.86 (2H, m).

Example 2 Synthesis of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Hydrazine hydrate (0.5 ml) was added to a methanol solution (60 ml) of 7-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-1-ethyl-3,3,5-tri methyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione (1.93 g). The mixture was stirred for 5.5 hours while heated under reflux. After cooled to room temperature, a 1N-sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and condensed under reduced pressure to give the title compound (1.2 g) as a yellow solid.

¹H-NMR (CDCl₃) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.47-1.58 (2H, m), 1.52 (3H, s), 1.62-1.73 (4H, m), 2.66 (2H, t, J=7.6 Hz), 2.76 (2H, t, J=7.0 Hz), 3.41 (3H, s), 3.71-3.84 (1H, m), 4.03-4.18 (1H, m), 7.02-7.09 (2H, m), 7.21 (1H, d, J=8.3 Hz).

Example 3 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

4-Pyridine carbaldehyde (0.15 ml) was added to a methanol solution (10 ml) of 7-(4-aminobutyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.51 g). The mixture was stirred for an hour at room temperature under nitrogen atmosphere. Sodium borohydride (0.2 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound (0.38 g) as a colorless oily matter.

¹H-NMR (CDCl₃) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.47-1.58 (2H, m), 1.53 (3H, s), 1.53-1.60 (2H, m), 1.62-1.71 (2H, m), 2.62-2.68 (4H, m), 3.40 (3H, s), 3.69-3.81 (3H, m), 4.03-4.19 (1H, m), 7.01 (1H, d, J=1.9 Hz), 7.06 (1H, dd, J=8.3, 1.9 Hz), 7.21 (1H, d, J=8.3 Hz), 7.25-7.28 (2H, m), 8.53-3.56 (2H, m).

Example 4 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(4-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}butyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

(2-Methyl-4-oxo-4H-furo[3,2-c]pyridin 5-yl)acetaldehyde (0.18 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione (0.38 g). The mixture was stirred for 30 minutes at room temperature. sodium triacetoxyborohydride (0.32 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→9:1). The purified product was condensed under reduced pressure. A 6N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (0.43 g) as a white solid.

¹H-NMR (DMSOd₆) δppm: 0.69 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.30 (3H, s), 1.56 (2H, br), 1.76 (2H, br), 2.38 (3H, s), 2.59 (2H, t, J=7.6 Hz), 3.13 (2H, br), 3.31 (3H, s), 3.22-3.38 (2H, m), 3.40-3.55 (1H, m), 3.99-4.08 (1H, m), 4.42 (2H, br), 4.64 (2H, br), 6.56 (1H, s), 6.75 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.38 (1H, d, J=8.4 Hz), 7.63 (1H, br), 8.22 (2H, br), 8.92 (2H, br).

Example 5 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{4-[(2-methylpyridin-3-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.52-1.61 (2H, m), 1.63-1.70 (2H, m), 2.56 (3H, s), 2.62-2.73 (4H, m), 3.40 (3H, s), 3.68-3.81 (3H, m), 4.02-4.19 (1H, m), 7.01-7.11 (3H, m), 7.20 (1H, d, J=8.3 Hz), 7.58-7.61 (1H, m), 8.38-8.40 (1H, m).

Example 6 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(4-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}butyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.70 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.31 (3H, s), 1.59 (2H, br), 1.74 (2H, br), 2.50 (3H, s), 2.61 (2H, t, J=7.6 Hz), 2.80 (2H, br), 3.10 (2H, br), 3.31 (3H, s), 3.55-3.70 (1H, m), 3.95-4.08 (1H, m), 4.37 (4H, br), 6.56 (1H, s), 6.82 (1H, br), 6.95 (1H, s), 7.13 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.39 (1H, d, J=8.4 Hz), 7.68 (1H, br), 7.81 (1H, br), 7.91 (1H, br), 8.71 (2H, br).

Example 7 Synthesis of 7-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 1 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.80 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.00-2.13 (2H, m), 2.72 (2H, t, J=7.7 Hz), 3.42 (3H, s), 3.68-3.73 (3H, m), 3.98-4.11 (1H, m), 7.07-7.10 (2H, m), 7.17-7.20 (1H, m), 7.70-7.75 (2H, m), 7.82-7.85 (2H, m).

Example 8 Synthesis of 7-(3-aminopropyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.84 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.54 (3H, s), 1.76 (2H, br), 1.74-1.91 (2H, m), 2.71 (2H, t, J=8.2 Hz), 2.84 (2H, t, J=7.0 Hz), 3.42 (3H, s), 3.81-3.95 (1H, m), 4.08-4.19 (1H, m), 7.09-7.14 (2H, m), 7.22-7.26 (1H, m).

Example 9 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.81 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.78-1.91 (2H, m), 2.66-2.74 (4H, m), 3.39 (3H, s), 3.71-3.89 (3H, m), 4.05-4.16 (1H, m), 7.02-7.10 (3H, m), 7.19-7.26 (2H, m), 8.52-8.56 (2H, m).

Example 10 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(3-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.69 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.05 (2H, br), 2.38 (3H, s), 2.60 (2H, br), 3.04 (2H, br), 3.31 (3H, s), 3.25-3.50 (2H, m), 3.40-3.65 (1H, m), 3.91-4.08 (1H, m), 4.38 (2H, br), 4.58 (2H, br), 6.55 (1H, s), 6.75 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.38 (1H, d, J=8.4 Hz), 7.63 (1H, d, J=7.4 Hz), 8.17 (2H, br), 8.88 (2H, br).

Example 11 Synthesis of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride

A 4N-hydrogen chloride ethyl acetate solution (6 ml) was added to an ethyl acetate solution (20 ml) of [2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl)ethyl]carbamic acid tert-butyl ester (0.38 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure to give the title compound (0.26 g) as a pale orange amorphous solid.

¹H-NMR (DMSO-d₆) δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.39 (3H, s), 2.91-3.00 (2H, m), 3.02-3.13 (2H, m), 3.38 (3H, s), 3.68-3.83 (1H, m), 3.95-4.11 (1H, m), 7.11-7.16 (1H, m), 7.23 (1H, br), 7.31-7.35 (1H, m), 8.06 (3H, br).

Example 12 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[(pyridin-4-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Triethylamine (0.1 ml) and 4-pyridine carbaldehyde (0.094 ml) were added to a methanol solution (10 ml) of 7-(2-aminoethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione hydrochloride (0.26 g). The mixture was stirred at room temperature for 1 hour. Sodium borohydride (0.11 g) was added, and the mixture was further stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was condensed under reduced pressure to give the title compound (0.21 g) as a colorless oily matter.

¹H-NMR (CDCl₃) δppm: 0.83 (3H, s), 1.86 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.82-2.94 (4H, m), 3.40 (3H, s), 3.73-3.85 (1H, m), 3.84 (2H, s), 4.02-4.18 (1H, m), 7.05-7.11 (2H, m), 7.20-7.26 (3H, m), 8.52-8.55 (2H, m).

Example 13 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[(2-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.52 (3H, s), 2.82-2.88 (2H, m), 2.93-2.99 (2H, m), 3.40 (3H, s), 3.75-3.82 (1H, m), 3.81 (3H, s), 4.11-4.18 (1H, m), 7.06-7.12 (2H, m), 7.22-7.26 (2H, m), 7.53-7.57 (1H, m), 8.37-8.40 (1H, m).

Example 14 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.33 (3H, s), 2.82-2.87 (2H, m), 2.93-2.99 (2H, m), 3.39 (3H, s), 3.75-3.84 (1H, m), 3.82 (3H, s), 4.10-4.20 (1H, m), 7.06-7.12 (3H, m), 7.21-7.26 (1H, m), 8.38 (1H, d, J=4.9 Hz), 8.41 (1H, s).

Example 15 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(2-{N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride.

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.69 (3H, s), 1.02 (3H, t, J=7.1 Hz), 1.31 (3H, s), 2.39 (3H, s), 3.08 (2H, br), 3.29 (3H, s), 3.11-3.42 (2H, m), 3.42-3.70 (3H, m), 3.91-4.10 (1H, m), 4.36 (2H, br), 4.57 (2H, br), 6.54 (1H, s), 6.71 (1H, d, J=7.2 Hz), 7.15-7.20 (1H, m), 7.30 (1H, s), 7.37-7.40 (1H, m), 7.60-7.63 (1H, m), 8.16 (2H, br), 8.86 (2H, br).

Example 16 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(2-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.70 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.50 (3H, s), 2.84 (2H, br), 3.14 (2H, br), 3.34 (3H, s), 3.25-3.45 (2H, m), 3.50-3.70 (1H, m), 3.90-4.08 (1H, m), 4.38 (2H, br), 4.47 (2H, br), 6.76 (1H, d, J=7.1 Hz), 6.93 (1H, s), 7.23 (1H, d, J=8.2 Hz), 7.36 (1H, s), 7.40 (1H, d, J=8.2 Hz), 7.69 (1H, br), 7.82 (1H, br), 7.90 (1H, d, J=2.1 Hz), 8.71 (2H, br).

Example 17 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.72 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.40 (3H, s), 2.51 (3H, s), 2.89 (4H, br), 3.31 (3H, s), 3.50 (2H, br), 3.72-3.77 (1H, m), 4.02-4.07 (1H, m), 4.42 (2H, br), 4.61 (2H, br), 6.54 (1H, s), 6.70 (1H, br), 7.23 (1H, br), 7.34 (1H, s), 7.40 (1H, br), 7.64 (1H, br), 7.86 (1H, br), 8.73 (2H, br).

Example 18 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.71 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.39 (3H, s), 2.51 (3H, s), 2.74 (2H, br), 3.15 (2H, br), 3.33 (3H, s), 3.51 (2H, br), 3.72-3.77 (1H, m), 4.02-4.07 (1H, m), 4.42 (2H, br), 4.75 (2H, br), 6.53 (1H, s), 6.70 (1H, br), 7.23-7.26 (1H, m), 7.36 (1H, s), 7.42-7.44 (1H, m), 7.64 (1H, br), 7.86 (1H, br), 8.76 (1H, br), 9.20 (1H, br).

Example 19 Synthesis of 7-aminomethyl-1,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

10% Palladium on carbon (0.1 g) was added to an acetic acid solution (20 ml) of 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (0.3 g), and catalytic reduction was carried out at room temperature under 4 atm. The catalyst was removed by celite filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound (0.17 g) as a yellowish white solid.

¹H NMR (CDCl₃) δppm: 3.28 (1H, d, J=12.4 Hz), 3.42 (3H, s), 3.44 (3H, s), 3.38-3.42 (1H, m), 3.94 (2H, s), 7.26-7.29 (3H, m).

Example 20 Synthesis of 7-aminomethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.43 (3H, s), 3.75-3.82 (1H, m), 3.93 (2H, s), 4.13-4.19 (1H, m), 7.20-7.23 (1H, m), 7.25-7.27 (2H, m).

Example 21 Synthesis of 7-aminomethyl-1,3,3,5-tetramethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.85 (3H, s), 1.54 (3H, s), 3.42 (3H, s), 3.44 (3H, s), 3.93 (2H, s), 7.18-7.26 (3H, m).

Example 22 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.69-3.82 (1H, m), 3.84 (2H, s), 3.87 (2H, s), 4.04-4.20 (1H, m), 7.23-7.26 (3H, m), 7.29-7.32 (2H, m), 8.56-8.58 (2H, m).

Example 23 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.56 (3H, s), 3.42 (3H, s), 3.77-3.88 (1H, m), 3.84 (2H, s), 3.88 (2H, s), 4.09-4.18 (1H, m), 7.11-7.15 (1H, m), 7.24-7.29 (3H, m), 7.63-7.65 (1H, m), 8.41-8.43 (1H, m).

Example 24 Synthesis of 1,5-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 2.59 (3H, s), 3.27 (1H, d, J=12.4 Hz), 3.37-3.43 (7H, m), 3.82 (2H, s), 3.86 (2H, s), 7.10-7.14 (1H, m), 7.23-7.26 (3H, m), 7.61-7.65 (1H, m), 8.39-8.42 (1H, m).

Example 25 Synthesis of 1,3,3,5-tetramethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.85 (3H, s), 1.54 (3H, s), 2.56 (3H, s), 3.43 (3H, s), 3.44 (3H, s), 3.82 (2H, s), 3.88 (2H, s), 7.11-7.15 (1H, m), 7.20-7.26 (3H, m), 7.62-7.64 (1H, m), 8.41-8.43 (1H, m).

Example 26 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[[[2-(pyridin-3-yl)ethyl]amino]methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Trimethyl orthoformate (9 ml) was added to a methanol solution (50 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.2 g) and 3-(2-aminoethyl)pyridine (1.0 g). The mixture was stirred at room temperature for 2 hours.

The reaction liquid was condensed under reduced pressure, and a methanol solution (50 ml) of the residue was cooled with ice. Sodium borohydride (0.34 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction liquid, followed by concentration under reduced pressure. The residue was extracted by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=9:1). The purified product was condensed under reduced pressure to give the title compound (2.5 g) as a colorless oily matter.

¹H NMR (CDCl₃) δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.80-2.90 (2H, m), 2.90-2.99 (2H, m), 3.39 (3H, s), 3.72-3.90 (1H, m), 3.83 (2H, s), 4.06-4.22 (1H, m), 7.14-7.20 (2H, m), 7.20-7.28 (2H, m), 7.54 (1H, td, J=2.0, 7.8 Hz), 8.45-8.53 (2H, m).

Example 27 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium borohydride (0.15 g) was added to a methanol solution (150 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (1.1 g) and 5-(2-aminoethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one (1.0 g), and the mixture was stirred at room temperature overnight. The reaction liquid was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound (1.1 g) as a colorless amorphous solid.

¹H NMR (CDCl₃) δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.15 (1H, br), 2.42 (3H, s), 3.02-3.10 (2H, m), 3.36 (3H, s), 3.75-3.81 (1H, m), 3.86 (2H, s), 4.09-4.20 (3H, m), 6.49 (1H, d, J=6.7 Hz), 6.53 (1H, d, J=1.9 Hz), 7.15-7.21 (4H, m).

Example 28 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.80 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.95 (2H, br), 3.36 (3H, s), 3.74-3.82 (1H, m), 3.86 (2H, br), 4.02-4.14 (1H, m), 4.20 (2H, br), 6.57 (1H, d, J=7.3 Hz), 6.96 (1H, d, J=2.0 Hz), 7.14-7.26 (4H, m), 7.50 (1H, d, J=2.0 Hz).

Example 29 Synthesis of 7,7′-azanediylbis(methylene)bis(1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4-dione)

10% Palladium on carbon (0.3 g) was added to an acetic acid solution (20 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile (1.4 g), and catalytic reduction was carried out at room temperature under 4 atm. The catalyst was removed by celite filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound (0.19 g) as a colorless oily matter.

¹H-NMR (CDCl₃) δppm: 0.84 (6H, s), 1.19 (6H, t, J=7.1 Hz), 1.54 (6H, s), 3.43 (6H, s), 3.71-3.92 (2H, m), 3.87 (4H, s), 4.01-4.18 (2H, m), 7.24-7.27 (6H, m).

Example 30 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}methyl)-1,5-dihydro benzo[b][1,4]diazepine-2,4-dione

5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.21 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.42 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound (0.47 g) as a white powder.

mp: 143 to 145° C.

Example 31 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 153 to 154° C.

Example 32 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 172 to 173° C.

Example 33 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[3-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)propyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.66 (3H, s), 1.04 (3H, br), 1.33 (3H, s), 2.29 (2H, br), 2.41 (3H, s), 2.80 (3H, br). 3.08 (2H, br), 3.33 (3H, s), 3.73-3.79 (1H, m), 3.93-4.01 (3H, m), 4.46 (2H, br), 4.57 (2H, br), 6.56 (1H, s), 6.67 (1H, d, J=6.2 Hz), 7.42-7.44 (1H, m), 7.48-7.59 (2H, m), 7.88 (2H, br), 8.76 (1H, br), 8.93 (1H, br).

Example 34 Synthesis of 7,7′-(pyridin-4-ylmethylazanediyl)bis(methylene)bis(1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4-dione) dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.69 (6H, s), 1.07 (6H, t, J=7.1 Hz), 1.32 (6H, s), 3.35 (6H, s), 3.74-3.81 (2H, m), 3.94-4.04 (2H, m), 4.52 (2H, br), 4.82 (4H, s), 7.45-7.47 (4H, m), 8.08 (2H, d, J=6.7 Hz), 8.05-8.40 (2H, m), 8.88 (2H, d, J=6.7 Hz).

Example 35 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.67 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.41-2.59 (5H, m), 2.83 (2H, br), 3.25 (3H, s), 3.61-3.83 (3H, m), 3.92-3.97 (1H, m), 4.16 (2H, br), 6.58 (1H, br), 7.22 (2H, br), 7.40 (2H, br), 7.48-7.63 (2H, m), 7.67-7.68 (1H, m), 7.71-7.75 (1H, m), 8.10-8.12 (1H, m), 8.24 (1H, br), 8.44 (1H, br).

Example 36 Synthesis of 1,5-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.38 (3H, s), 2.51 (3H, s), 2.54 (2H, br), 2.75 (2H, br), 3.05 (1H, d, J=12.4 Hz), 3.26 (6H, s), 3.32 (1H, d, J=12.4 Hz), 3.75 (2H, br), 4.14 (2H, br), 6.45 (1H, br), 6.63 (1H, br), 7.24 (1H, br), 7.33 (1H, br), 7.50 (2H, br), 7.68 (1H, br), 8.25 (1H, br), 8.56 (1H, br).

Example 37 Synthesis of 1,3,3,5-tetramethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.70 (3H, s), 1.34 (3H, s), 2.51 (3H, s), 2.55 (2H, br), 2.82 (2H, br), 3.30 (6H, s), 3.78 (2H, br), 4.19 (2H, br), 6.73 (1H, br), 6.88 (1H, br), 7.31 (3H, br), 7.60 (2H, br), 7.91 (1H, d, J=2.0 Hz), 8.26 (1H, br), 8.56 (1H, br).

Example 38 Synthesis of 1,3,3,5-tetramethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.70 (3H, s), 1.34 (3H, s), 2.41 (3H, s), 2.51 (3H, s), 2.56 (2H, br), 2.79 (2H, br), 3.30 (6H, s), 3.77 (2H, br), 4.15 (2H, br), 6.46 (1H, br), 6.63 (1H, br), 7.31 (3H, br), 7.50 (1H, br), 7.68 (1H, br), 8.24 (1H, br), 8.56 (1H, br).

Example 39 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.92 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of (2-pyridine 3-ylethyl)pyridin-4-ylmethylamine (0.81 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.90 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (0.83 g) as a white solid

¹H-NMR (DMSO-d₆) δppm: 0.68 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.33 (3H, s), 3.00 (2H, br), 3.32 (3H, s), 3.10-3.45 (4H, m), 3.74-3.79 (1H, m), 3.94-4.00 (3H, m), 7.43 (2H, br), 7.98-8.02 (2H, m), 8.45 (1H, d, J=8.0 Hz), 8.82-8.88 (6H, m).

Example 40 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzamide hydrochloride

Benzoyl chloride (0.13 ml) was added to an acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38 g) and triethylamine (0.17 ml) under ice cooling. The mixture was stirred at room temperature overnight. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=91:9). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.87 ml) was added to an isopropyl alcohol solution (10 ml) of the residue, and the liquid was condensed under reduced pressure. The residue was recrystallized from the ethanol-ether mixture to give the title compound (0.26 g) as a pale brown white powder.

¹H NMR (DMSO-d₆) δppm: 0.73 (3H, bs), 0.98-1.14 (3H, m), 1.34 (3H, s), 2.74-3.94 (8H, m), 3.94-4.11 (1H, m), 4.52 and 4.82 (2H, bs), 6.90-7.60 (8H, m), 7.60-9.10 (4H, m).

Example 41 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-4-methyl-N-(2-pyridin-3-ylethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.

¹H NMR (DMSO-d₆) δppm: 0.73 (3H, s), 1.09 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.31 (3H, s), 2.88-3.94 (8H, m), 3.94-4.11 (1H, m), 4.35-5.05 (2H, m), 6.88-7.63 (7H, m), 7.63-9.10 (4H, m).

Example 42 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)benzenesulfonamide

Triethylamine (0.15 ml) was added to a acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-yl-ethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.35 g). The mixture was cooled with ice. Benzenesulphonyl chloride (0.13 ml) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. Water was added to the residue, followed by extraction by ethyl acetate.

The organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=30:70). The purified product was condensed under reduced pressure, and the residue was recrystallized from the ethyl acetate-ether mixture to give the title compound (0.1 g) as a white powder.

mp: 143.2 to 146.4° C.

Example 43 Synthesis of 7-{[N-benzyl-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆) δppm: 0.72 (3H, s), 1.05 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.59-3.72 (8H, m), 3.72-3.94 (1H, m), 3.94-4.11 (1H, m), 4.33-4.65 (3H, m), 6.85-8.18 (10H, m), 8.30-8.77 (2H, m), 11.17 (1H, bs).

Example 44 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 160 to 161° C.

Example 45 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 171 to 174° C.

Example 46 Synthesis of 7-({N-(2,6-dimethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 148 to 149° C.

Example 47 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(6-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 123 to 125° C.

Example 48 Synthesis of N-[2-({[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-7-yl)methyl][2-(pyridin-3-yl)ethyl]amino}methyl)phenyl]methanesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆) δppm: 0.71 and 0.73 (3H, s), 0.90-1.20 (3H, m), 1.33 (3H, s), 2.69-2.80 (1H, bs), 2.85 (2H, bs), 2.92-3.10 (4H, m), 3.20-3.70 (3H, m), 3.70-3.96 (3H, m), 3.96-4.10 (1H, m), 4.46-4.73 (2H, m), 7.00-7.70 (7H, m), 7.70-8.30 (2H, m), 8.52-8.80 (2H, m), 9.30-9.59 (1H, m), 10.90 (1H, bs).

Example 49 Synthesis of 7-{[N-(2,4-dimethylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆) δppm: 0.73 (3H, s), 1.09 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.30 (3H, bs), 2.59 (3H, s), 2.65-5.20 (13H, m), 6.32-8.07 (4H, m), 8.16-8.40 (1H, m), 8.66-8.90 (2H, m), 11.91 (1H, bs).

Example 50 Synthesis of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-methyl-N-(2-pyridin-3-ylethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.

¹H NMR (DMSO-d₆) δppm: 0.71 and 0.75 (3H, s), 1.00-1.12 (3H, m), 1.32 and 1.34 (3H, s), 2.03 and 2.04 (3H, s), 2.85-5.50 (8H, m), 3.26 and 3.34 (3H, s), 6.86 (0.4H, d, J=7.8 Hz), 7.05-7.98 (8.3H, m), 8.39 (0.9H, bs), 8.63 (0.4H, bs), 8.74 (0.5H, bs), 8.87 (0.5H, bs).

Example 51 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.72 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.68 (3H, br), 3.10 (2H, br), 3.34 (3H, s), 3.18-3.60 (4H, m), 3.74-3.90 (3H, m), 3.99-4.05 (1H, m), 7.49 (2H, br), 7.73 (1H, br), 7.87 (1H, br), 7.98-8.01 (1H, br), 8.45 (1H, br), 8.68-8.70 (2H, m), 8.81 (1H, d, J=5.5 Hz), 8.89 (1H, br).

Example 52 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(thiazol-2-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 171 to 172° C.

Example 53 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(thiazol-2-ylmethyl)amino}methyl)-1,5-dihydro benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 146 to 147° C.

Example 54 Synthesis of 7-{[N-(2,6-dimethylpyridin-3-ylmethyl)-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.68 (3H, s), 1.02 (3H, t, J=7.1 Hz), 1.32 (3H, s), 3.32 (9H, s), 3.32 (3H, s), 3.67 (2H, br), 3.60-3.82 (1H, m), 3.78 (2H, br), 3.82 (2H, br), 3.97-4.04 (1H, m), 7.28 (1H, br), 7.34 (1H, br), 7.39-7.41 (1H, m), 7.67 (1H, d, J=7.8 Hz), 7.82-7.85 (1H, m), 8.43 (1H, br), 8.56 (1H, br), 8.61 (1H, br).

Example 55 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 0.67 (3H, s), 1.01 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.48 (3H, s), 2.70 (3H, s), 3.31 (3H, s), 3.63-3.75 (3H, m), 3.87 (4H, br), 3.95-4.08 (1H, m), 7.25 (1H, m), 7.34 (1H, m), 7.38-7.40 (1H, m), 7.81-7.86 (2H, m), 8.55 (1H, br), 8.62 (1H, d, J=5.2 Hz), 8.69 (1H, d, J=5.9 Hz), 8.86 (1H, br).

Example 56 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(4-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 39 using appropriate starting materials.

White powder

¹H NMR (DMSO-d₆) δppm: 0.70 (3H, s), 1.03 (3H, br), 1.33 (3H, s), 2.33 (3H, br), 2.86 (2H, br), 3.10 (2H, br), 3.32 (3H, s), 3.31-3.41 (1H, m), 3.77 (4H, br), 4.00-4.06 (1H, m), 7.20 (1H, br), 7.43 (2H, br), 7.80 (1H, br), 7.97 (1H, br), 8.41 (1H, br), 8.70 (2H, br), 8.79-8.81 (2H, m).

Example 57 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylthiazol-5-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 161 to 162° C.

Example 58 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 188 to 189° C.

Example 59 Synthesis of 2-methyl-2H-pyrazole-3-sulfonic acid N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl) amide

The synthesis of the title compound was performed in the same manner as in Example 42 using appropriate starting materials.

White powder (ethyl acetate)

mp: 123 to 124° C.

Example 60 Synthesis of 7-{[N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

White powder (diethyl ether)

mp: 136 to 145° C.

Example 61 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-4-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 39 using appropriate starting materials.

¹H NMR (DMSO-d₆) δppm: 0.71 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.71 (5H, br), 3.20-3.39 (3H, m), 3.37 (3H, s), 3.55 (2H, br), 3.77 (2H, br), 3.99-4.04 (1H, m), 7.31 (1H, br), 7.47 (2H, br), 7.85 (2H, br), 7.95 (2H, br), 8.68 (1H, br), 8.85 (2H, br).

Example 62 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 164 to 165° C.

Example 63 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 181 to 183° C.

Example 64 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 134 to 136° C.

Example 65 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(thiazol-2-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.43 (3H, s), 3.74-3.84 (1H, m), 3.92 (2H, s), 4.09-4.18 (3H, m), 7.25-7.27 (3H, m), 7.30 (1H, d, J=3.3 Hz), 7.75 (1H, d, J=3.3 Hz).

Example 66 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.38 (3H, s), 3.42 (3H, s), 3.74-3.84 (1H, m), 3.83 (2H, s), 3.87 (2H, s), 4.09-4.18 (1H, m), 7.09 (1H, d, J=4.9 Hz), 7.24-7.27 (3H, m), 8.39 (1H, d, J=4.9 Hz), 8.46 (1H, s).

Example 67 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃) δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.40 (3H, s), 3.43 (3H, s), 3.75-3.84 (1H, m), 3.86 (2H, s), 3.97 (2H, s), 4.09-4.18 (1H, m), 7.22-7.28 (3H, m), 8.65 (1H, s).

Example 68 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 164-165° C.

Example 69 Synthesis of 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 193-195° C.

Example 70 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 203-204° C.

Example 71 Synthesis of 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 181-182° C.

Example 72 Synthesis of 7-({N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(thiazol-2-ylmethyl)amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 157-159° C.

Example 73 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(4-m ethylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.68 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.30 (3H, s), 2.70 (3H, s), 3.32 (3H, s), 3.68 (2H, s), 3.67-3.76 (1H, m), 3.84 (4H, br), 3.97-4.06 (1H, m), 7.25-7.27 (1H, m), 7.34 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.84 (1H, dd, J=6.0, 7.7 Hz), 8.48-8.50 (1H, m), 8.62 (1H, d, J=5.5 Hz), 8.95-8.97 (1H, m).

Example 74 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{(N-[(1-methyl-1H-indazol-3-yl)methyl]-N-[2-(pyridin-3-yl)ethyl]amino)methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (D₂O), δppm: 0.73 (3H, s), 1.11 (3H, t, J=7.0 Hz), 1.41 (3H, s), 3.15-3.29 (2H, m), 3.30 (3H, s), 3.38-3.58 (2H, m), 3.68-3.88 (1H, m), 4.00-4.20 (1H, m), 4.04 (3H, s), 4.37 (2H, bs), 4.44 (2H, bs), 7.08-7.21 (1H, m), 7.35 (1H, d, J=7.8 Hz), 7.39-7.60 (5H, m), 7.65 (1H, dd, J=6.0, 7.5 Hz), 8.10 (1H, d, J=7.8 Hz), 8.35-8.49 (2H, m).

Example 75 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methyloxazol-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (D₂O), δppm: 0.79 (3H, s), 1.14 (3H, t, J=7.0 Hz), 1.43 (3H, s), 2.48 (3H, s), 3.21-3.33 (2H, m), 3.37-3.52 (2H, m), 3.40 (3H, s), 3.77-3.93 (1H, m), 4.07-4.21 (1H, m), 4.36 (2H, s), 4.47 (2H, dd, J=13.6, 22.0 Hz), 7.50 (1H, dd, J=1.4, 8.4 Hz), 7.54-7.60 (1H, m), 7.63 (1H, d, J=8.4 Hz), 7.73 (1H, dd, J=5.6, 7.9 Hz), 7.95 (1H, bs), 8.09 (1H, d, J=7.9 Hz), 8.54 (1H, bs), 8.58 (1H, d, J=5.6 Hz).

Example 76 Synthesis of 7-{[N-[2-(2,3-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-dd, δppm: 0.70 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.12 (3H, s), 2.31 (3H, s), 2.45 (3H, br), 2.77 (2H, br), 3.28 (3H, s), 3.71-3.83 (3H, m), 3.94-4.07 (3H, m), 4.08 (2H, br), 6.54 (1H, br), 7.24 (1H, br), 7.35 (2H, br), 7.42 (1H, br), 7.67 (1H, br), 8.26 (1H, br), 8.52 (1H, br).

Example 77 Synthesis of 7-{[N-[2-(2,3-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.70 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.11 (3H, s), 2.24 (3H, br), 2.31 (3H, s), 2.80 (2H, br), 3.28 (3H, s), 3.71-3.84 (3H, m), 3.94-4.11 (5H, m), 6.50 (1H, br), 7.24 (1H, br), 7.36 (2H, br), 7.40 (1H, br), 7.59 (1H, br), 8.59 (1H, br), 8.64 (1H, br).

Example 78 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methylpyridin-3-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 39 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.72 (3H, s), 1.05 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.70 (8H, br), 3.34 (3H, br), 3.78 (3H, br), 4.01-4.20 (5H, m), 7.47 (1H, br), 7.52 (1H, br), 7.85 (2H, br), 8.35 (2H, br), 8.65 (2H, br), 9.00 (1H, br).

Example 79 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methylpyridin-3-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.73 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.43 (3H, s), 2.46 (3H, s), 3.36 (5H, br), 3.45 (2H, br), 3.77-3.88 (1H, m), 4.00-4.12 (1H, m), 4.45 (2H, br), 4.65 (2H, br), 7.52-7.54 (1H, m), 7.60 (1H, br), 7.88 (1H, d, J=6.0 Hz), 7.90 (1H, br), 7.71 (1H, d, J=6.0 Hz), 8.77 (1H, s), 9.15 (1H, s).

Example 80 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-methylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.73 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.11 (3H, s), 2.45 (3H, s), 3.36 (5H, br), 3.50 (2H, br), 3.50-3.82 (4H, m), 3.95-4.08 (1H, m), 4.45 (2H, br), 4.53 (2H, br), 6.51 (1H, br), 7.56 (1H, br), 7.61 (1H, br), 7.87-7.89 (1H, m), 8.02 (1H, m), 8.71 (1H, d, J=5.8 Hz), 8.78 (1H, s).

Example 81 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methylpyridin-3-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-dd, δppm: 0.74 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.41 (3H, s), 2.65 (3H, s), 3.36 (7H, br), 3.70-3.79 (1H, m), 3.95-4.08 (1H, m), 4.47 (2H, br), 4.73 (2H, br), 7.54 (1H, br), 7.60 (1H, br), 7.87 (1H, dd, J=7.8, 5.7 Hz), 7.92 (1H, br), 8.33 (1H, d, J=7.8 Hz), 8.66 (1H, d, J=5.7 Hz), 9.12 (1H, s).

Example 82 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-dd, δppm: 0.75 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.35 (3H, s), 2.12 (3H, s), 2.67 (3H, s), 3.36 (5H, br), 3.43 (2H, br), 3.70-3.90 (4H, m), 4.00-4.08 (1H, m), 4.45 (2H, br), 4.50 (2H, br), 6.50 (1H, br), 7.55-7.57 (1H, m), 7.61 (1H, br), 7.85-7.88 (1H, m), 7.94 (1H, br), 8.36 (1H, br), 8.67 (1H, d, J=5.6 Hz).

Example 83 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 152-153° C.

Example 84 Synthesis of 1-ethyl-7-({N-(4-methoxypyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.43 (3H, s), 2.77-2.87 (2H, m), 3.29 (3H, s), 3.61 (1H, d, J=14.3 Hz), 3.68-3.74 (2H, m), 3.78 (1H, d, J=14.3 Hz), 3.86 (3H, s), 3.97-4.08 (1H, m), 4.09-4.19 (3H, m), 6.43-6.46 (2H, m), 6.78 (1H, d, J=5.8 Hz), 7.00 (2H, br), 7.05 (1H, s), 7.10 (1H, d, J=7.3 Hz), 8.39-8.40 (2H, m).

Example 85 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-trifluoromethylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 162-164° C.

Example 86 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.423 g) and acetic acid (0.14 g) were added to a 1,2-dichloroethane solution (10 ml) of N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amine (0.36 g) The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.48 g) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→50:50). The purified product was condensed under reduced pressure. The residue was washed with diethyl ether, and dried to give the title compound (0.37 g) as a white powder.

mp: 118-120° C.

Example 87 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(5-trifluoromethylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 138-140° C.

Example 88 Synthesis of 1-ethyl-7-({N-(5-fluoropyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 144-146° C.

Example 89 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 153-154° C.

Example 90 Synthesis of 1-Ethyl-7-({N-(3-fluoropyridin-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diethyl ether)

mp: 149-151° C.

Example 91 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-methyl-2H-pyrazol-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (D₂O), δppm: 0.79 (3H, s), 1.11 (3H, t, J=7.0 Hz), 1.43 (3H, s), 3.09-3.70 (5H, m), 3.39 (3H, s), 3.45 (2H, s), 3.70-3.94 (1H, m), 3.94-4.59 (5H, m), 6.3-6.57 (1H, m), 7.30-7.65 (4H, m), 7.82-8.06 (1H, m), 8.15-8.47 (1H, m), 8.51 (1H, bs), 8.54-8.74 (1H, m).

Example 92 Synthesis of 1-ethyl-7-{[N-(1H-indol-7-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

White powder (ethanol)

mp: 155-167.8° C.

Example 93 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(4-methylpyridin-3-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.32 (3H, s), 2.94-2.96 (2H, m), 3.00 (2H, br), 3.42 (3H, s), 3.74-3.74 (1H, m), 3.96 (2H, br), 4.04-4.11 (1H, m), 7.07 (1H, d, J=4.9 Hz), 7.26-7.28 (2H, m), 7.34 (1H, br), 8.33 (1H, d, J=4.9 Hz), 8.38 (1H, s).

Example 94 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[2-(2-methylpyridin-3-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.55 (3H, s), 2.85-2.93 (4H, m), 3.41 (3H, s), 3.75-3.83 (1H, m), 3.86 (2H, s), 4.11-4.17 (1H, m), 7.08 (1H, dd, J=7.6, 4.8 Hz), 7.19-7.21 (2H, m), 7.24-7.26 (1H, m), 7.44 (1H, dd, J=7.6, 1.6 Hz), 8.37 (1H, dd, 4.8, 1.6 Hz).

Example 95 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methyloxazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.69 (3H, s), 1.06 (3H, t, J=7.1 Hz), 1.33 (3H, s), 2.395 (3H, s), 2.404 (3H, s), 3.32 (3H, s), 3.47 (2H, br), 3.74-3.81 (1H, m), 3.95-4.06 (1H, m), 4.23 (2H, br), 4.37 (4H, br), 6.55 (1H, s), 6.76 (1H, d, J=7.4 Hz), 7.48 (2H, br), 7.57 (1H, d, J=7.4 Hz), 7.67 (1H, br), 8.14 (1H, br).

Example 96 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(oxazol-5-ylmethyl)amino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.66 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.39 (3H, s), 3.21 (3H, s), 3.28-3.49 (2H, m), 3.74 (1H, br), 3.91-3.97 (1H, m), 4.20 (6H, br), 6.69 (1H, s), 6.69-6.71 (1H, m), 7.11-7.31 (4H, m), 7.54 (1H, d, J=7.5 Hz), 8.33 (1H, br).

Example 97 Synthesis of 7-({N-(2,4-dimethylthiazol-5-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Pale yellow powder

mp: 187-188° C.

Example 98 Synthesis of 7-{[N-(2-chloropyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white powder

mp: 183-187° C.

Example 99 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)-N-(quinolin-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white powder

mp: 136-141° C.

Example 100 Synthesis of 7-{[N-[2-(2,6-dimethylpyridin-3-yl)ethyl]-N-(4-methylthiazol-5-yl methyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 136-137° C.

Example 101 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 139-140° C.

Example 102 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 145-147° C.

Example 103 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 138-142° C.

Example 104 Synthesis of 7-{[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 144-145° C.

Example 105 Synthesis of 7-{[N-[2-(2,3-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 148-150° C.

Example 106 Synthesis of 1-ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 125-127° C.

Example 107 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 193-195° C.

Example 108 Synthesis of 7-({N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-[2-(2,6-dimethylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white powder

¹H NMR (DMSO-d₆), δppm: 0.75 (3H, s), 1.07 (3H, t, J=7.1 Hz), 1.35 (3H, s), 2.11 (3H, s), 2.65 (3H, br), 2.71 (3H, br), 3.36 (5H, br), 3.50 (3H, s), 3.60-3.82 (3H, m), 4.00-4.10 (1H, m), 4.44 (2H, br), 4.53 (2H, br), 6.50 (1H, br), 7.57-7.67 (2H, m), 7.69 (1H, d, J=7.9 Hz), 8.00 (1H, br), 8.23 (1H, br).

The following compounds shown in Examples 109 to 308 can be prepared by the same manner as mentioned above or a conventional manner using appropriate starting materials.

Example 109 1-Ethyl-3,3,5-trimethyl-7-{[oxazol-5-ylmethyl-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 110 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiazol-2-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 111 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiazol-5-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 112 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiazol-4-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 113 1-Ethyl-3,3,5-trimethyl-7-{[(4-methyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 114 7-{[(4,5-Dimethyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 115 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-pyridin-4-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 116 1-Ethyl-7-{[(3-fluoro-pyridin-4-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 117 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-pyridin-4-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 118 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 119 7-{[[2-(2,6-Dimethyl-pyridin-3-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b ][1,4]diazepine-2,4-dione Example 120 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-pyridin-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 121 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-(4-trifluoromethyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 122 1-Ethyl-7-{[(2-methoxy-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 123 7-{[(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 124 1-Ethyl-7-{[(3-hydroxy-benzyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 125 1-Ethyl-7-{[furan-2-ylmethyl-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 126 1-Ethyl-7-{[furan-3-ylmethyl-(2-pyridin-3-yl-ethyl)-amino]-methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 127 1-Ethyl-3,3,5-trimethyl-7-{[(5-methyl-furan-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 128 1-Ethyl-3,3,5-trimethyl-7-{[(2-methyl-furan-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 129 7-{[(4,5-Dimethyl-furan-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 130 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 131 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-thiophen-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 132 1-Ethyl-3,3,5-trimethyl-7-{[(2-pyridin-3-yl-ethyl)-thiophen-2-ylmethyl-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 133 7-{[(4,5-Dimethyl-thiophen-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 134 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 135 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-thiazol-5-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 136 1-Ethyl-3,3,5-trimethyl-7-{2-[(2-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 137 1-Ethyl-3,3,5-trimethyl-7-{2-[(4-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 138 1-Ethyl-3,3,5-trimethyl-7-{2-[(3-methyl-pyridin-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 139 7-{2-[(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 140 N-(2-{[[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-(2-pyridin-3-yl-ethyl)-amino]-methyl}-phenyl)-methanesulfonamide Example 141 7-{2-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 142 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-thiazol-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 143 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-thiazol-5-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 144 1-Ethyl-3,3,5-trimethyl-7-{3-[(2-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 145 1-Ethyl-3,3,5-trimethyl-7-{3-[(4-methyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 146 1-Ethyl-3,3,5-trimethyl-7-{3-[(3-methyl-pyridin-2-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 147

N-(2-{[[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-(2-pyridin-3-yl-ethyl)-amino]-methyl}-phenyl)-methanesulfonamide

Example 148 7-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 149 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-3-ylmethyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 150 1-Ethyl-3,3,5-trimethyl-7-({oxazol-5-ylmethyl-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 151 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 152 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 153 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 154 7-({(4,5-Dimethyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 155 7-({(2,4-Dimethyl-thiazol-5-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 156 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-pyridin-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 157 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-4-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 158 1-Ethyl-7-({(3-fluoro-pyridin-4-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 159 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-pyridin-4-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 160 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-pyridin-3-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 161 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-pyridin-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 162 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-trifluoromethyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 163 1-Ethyl-7-({(2-methoxy-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 164 7-({(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 165 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 166 1-Ethyl-7-({(3-hydroxy-benzyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 167 1-Ethyl-7-({furan-2-ylmethyl-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl) ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 168 1-Ethyl-7-({furan-3-ylmethyl-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl) ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 169 1-Ethyl-3,3,5-trimethyl-7-({(5-methyl-furan-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 170 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-furan-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 171 7-({(4,5-Dimethyl-furan-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 172 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 173 7-({(4,5-Dimethyl-thiophen-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 174 1-Ethyl-3,3,5-trimethyl-7-({[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiophen-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 175 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-thiophen-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 176 7-({(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 177 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-oxazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 178 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-5-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 179 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 180 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 181 7-({(4,5-Dimethyl-thiazol-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 182 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-4-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 183 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-pyridin-3-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 184 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 185 1-Ethyl-7-({(2-methoxy-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 186 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 187 1-Ethyl-7-({(3-hydroxy-benzyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 188 1-Ethyl-7-({furan-2-ylmethyl-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 189 1-Ethyl-7-({furan-3-ylmethyl-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 190 1-Ethyl-3,3,5-trimethyl-7-({(5-methyl-furan-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 191 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-furan-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 192 7-({(4,5-Dimethyl-furan-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 193 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 194 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-thiophen-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 195 1-Ethyl-3,3,5-trimethyl-7-{[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-thiophen-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 196 7-({(4,5-Dimethyl-thiophen-2-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 197 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 198 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 199 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 200 1-Ethyl-3,3,5-trimethyl-7-{[[2-(3-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 201 7-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 202 7-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 203 7-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 204

N-(2-{[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-amino]-methyl}-phenyl)-methanesulfonamide

Example 205 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 206 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-thiazol-5-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 207 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 208 1-Ethyl-3,3,5-trimethyl-7-(2-{(3-methyl-pyridin-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 209

N-[2-({[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide

Example 210 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 211 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 212 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 213 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 214 7-(2-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 215

N-[2-({[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide

Example 216 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 217 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 218 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 219 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 220 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 221 1-Ethyl-3,3,5-trimethyl-7-{2-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 222

N-[2-({[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide

Example 223 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 224 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 225 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 226 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 227 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 228 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 229

N-[2-({[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-[2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide

Example 230 7-{2-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amino]-ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 231 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-thiazol-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 232 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-thiazol-5-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 233 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 234 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 235 1-Ethyl-3,3,5-trimethyl-7-(3-{(3-methyl-pyridin-2-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 236

N-[2-({[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide

Example 237 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 238 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 239 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 240 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 241 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 242 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 243 7-{3-[(2,6-Dimethyl-pyridin-3-ylmethyl)-(2-pyridin-3-yl-ethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 244 7-(3-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 245 N-[2-({[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 246 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 247 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 248 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 249 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 250 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 251 1-Ethyl-3,3,5-trimethyl-7-{3-[[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 252 N-[2-({[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 253 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 254 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-2-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 255 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-thiazol-5-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 256 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 257 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 258 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 259

N-[2-({[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)-propyl]-amino}-methyl)-phenyl]-methane sulfonamide

Example 260 7-{3-[[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amino]-propyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 261 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 262 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 263 1-Ethyl-3,3,5-trimethyl-7-{[[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 264 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 265 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-ethyl]-(2-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 266 1-Ethyl-3,3,5-trimethyl-7-{[[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-ethyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 267 1-Ethyl-3,3,5-trimethyl-7-({oxazol-5-ylmethyl-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 268 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiazol-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 269 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiazol-5-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 270 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiazol-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 271 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-thiazol-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 272 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b ][1,4]diazepine-2,4-dione Example 273 7-({(4,5-Dimethyl-thiazol-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 274 7-({(2,4-Dimethyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 275 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-pyridin-4-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 276 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-4-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 277 1-Ethyl-7-({(3-fluoro-pyridin-4-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 278 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-pyridin-4-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 279 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-pyridin-3-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 280 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 281 1-Ethyl-3,3,5-trimethyl-7-{[[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-(4-trifluoromethyl-pyridin-3-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 282 1-Ethyl-7-({(2-methoxy-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 283 7-({(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 284 N-[2-({(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-phenyl]-methanesulfonamide Example 285 1-Ethyl-7-({(3-hydroxybenzyl)-[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 286 1-Ethyl-7-({furan-2-ylmethyl-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 287 1-Ethyl-7-({furan-3-ylmethyl-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 288 1-Ethyl-3,3,5-trimethyl-7-({(5-methyl-furan-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 289 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-furan-3-ylmethyl)-[2-(2-oxo-3,4-divinyl-2H-pyridin-1-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 290 7-({(4,5-Dimethyl-furan-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 291 1-Ethyl-3,3,5-trimethyl-7-{[[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-(5-trifluoromethyl-furan-2-ylmethyl)-amino]-methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 292 1-Ethyl-3,3,5-trimethyl-7-({[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-thiophen-2-ylmethyl-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 293 1-Ethyl-3,3,5-trimethyl-7-({(3-methyl-thiophen-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 294 7-({(4,5-Dimethyl-thiophen-2-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 295 7-({(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 296 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 297 1-Ethyl-3,3,5-trimethyl-7-(2-{(4-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 298 1-Ethyl-3,3,5-trimethyl-7-(2-{(2-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 299 7-(2-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 300 7-(2-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 301 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-thiazol-5-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 302 1-Ethyl-3,3,5-trimethyl-7-(3-{(4-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 303 1-Ethyl-3,3,5-trimethyl-7-(3-{(2-methyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 304 7-(3-{(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 305 7-(3-{(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(1-oxo-2H-isoquinolin-2-yl)-ethyl]-amino}-propyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 306 1-Ethyl-3,3,5-trimethyl-7-({(2-methyl-pyridin-3-ylmethyl)-[2-(2-oxo-2H-quinolin-1-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 307 1-Ethyl-3,3,5-trimethyl-7-({(4-methyl-pyridin-3-ylmethyl)-[2-(2-oxo-2H-quinolin-1-yl)-ethyl]-amino}-methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 308 7-({(2,6-Dimethyl-pyridin-3-ylmethyl)-[2-(2-oxo-2H-quinolin-1-yl)-ethyl]-amino}-methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 309 7-{[N-(4-Chloropyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white powder

mp: 200-205° C. (dec.)

Example 310 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 161-165° C.

Example 311 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 144-146° C.

Example 312 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 127-128° C.

Example 313 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 197-199° C.

Example 314 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 190-193° C.

Example 315 1-Ethyl-3,3,5-trimethyl-7-{[N-(4-methylthiazol-2-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white amorphous

¹H NMR (D₂O), δppm: 0.75 (3H, s), 1.10 (3H, t, J=7.2 Hz), 1.42 (3H, s), 2.39 (3H, s), 3.25-3.36 (4H, m), 3.37 (3H, s), 3.73-3.87 (1H, m), 4.07-4.22 (3H, m), 4.41 (2H, s), 7.18 (1H, d, J=1.0 Hz), 7.32-7.38 (1H, m), 7.38-7.43 (1H, m), 7.49 (1H, d, J=8.3 Hz), 7.99 (1H, dd, J=6.0, 8.0 Hz), 8.44 (1H, d, J=8.3 Hz), 8.66-8.73 (2H, m)

Example 316 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 123-125° C.

Example 317 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 127-129° C.

Example 318 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 104-111° C.

Example 319 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride

4 M HCl/AcOEt (90 μl) was added to an ethyl acetate solution (1 ml) of 1-ethyl-7-({(2-methoxymethylpyridin-3-ylmethyl)-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (26 mg) and stirred for 5 minutes at room temperature. The resulting precipitate was collected and washed with ether to give the title compound as a white powder (14 mg).

¹H NMR (DMSO-d₆), 8 ppm: 0.75 (3H, s), 1.05 (3H, t, J=7.1 Hz), 1.35 (3H, s), 2.16 (3H, s), 3.27-3.33 (8H, m), 3.70-4.40 (6H, m), 4.52 (2H, br), 4.65 (2H, br), 6.93 (1H, s), 7.28-7.48 (4H, m), 7.72-7.84 (1H, m), 7.97 (1H, s), 8.35 (1H, br), 8.53-8.65 (1H, m).

Example 320 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-2-trifluoromethyl-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 132-134° C.

Example 321 1-Ethyl-3,3,5-trimethyl-7-({N-(3-methyl-3H-imidazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 106-108° C.

Example 322 1-Ethyl-3,3,5-trimethyl-7-({N-(3-methyl-3H-imidazol-4-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 100-105° C.

Example 323 1-Ethyl-7-({N-[2-(2-methoxymethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 123-126° C.

Example 324 1-Ethyl-7-({N-[2-(2-methoxymethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

pale yellow powder

¹H NMR (DMSO-d₆), δppm: 0.69 (3H, s), 1.01 (3H, t, J=7.1 HZ), 1.33 (3H, s), 2.22 (3H, s), 2.80 (2H, s), 3.27 (3H, s), 3.30 (3H, s), 3.61-4.05 (6H, m), 4.12 (2H, br), 4.48 (2H, s), 6.63 (1H, d, J=7.4 Hz), 6.78 (1H, s), 7.22 (1H, br), 7.32-7.33 (2H, m), 7.54 (1H, d, J=7.0 Hz), 7.61 (1H, d, J=5.7 Hz), 8.61 (1H, d, J=5.7 Hz), 8.63 (1H, s).

Example 325 7-({N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methoxymethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

ivory powder

¹H NMR (DMSO-d₆), δppm: 0.69 (3H, s), 1.03 (3H, t, J=7.1 Hz), 1.32 (3H, s), 2.04 (3H, s), 2.71 (2H, br), 3.27 (3H, s), 3.30 (3H, br), 3.45-4.00 (6H, m), 3.85 (3H, s), 4.39-4.63 (4H, m), 6.44 (1H, br), 6.61-7.02 (2H, m), 7.05-7.95 (4H, m).

Example 326 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-phenyl-N-(2-pyridin-3-ylethyl)acetamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.

white amorphous

¹H NMR (DMSO-d₆), δppm: 0.70 and 0.73 (3H, s), 0.95-1.13 (3H, m), 1.32 and 1.33 (3H, s), 2.91-3.03 (2H, m), 3.22 and 3.25 (3H, s), 3.50-3.82 (5H, m), 3.96-4.09 (1H, m), 4.56-4.74 (2H, m), 7.04-7.34 (7H, m), 7.42-7.52 (1H, m), 7.78 (1H, bs), 8.19 (1H, bs), 8.65-8.77 (2H, m)

Example 327

N-[2-({N′-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 161-163° C.

Example 328 7-({N-(2-Chloropyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 158.7-160.8° C.

Example 329 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbonitrile

2-Chloro-3-({(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine (0.3 g), zinc cyanide (120 mg), tris(dibenzylideneacetone)dipalladium (24 mg), 1,1′-bis(diphenylphosphino)ferrocene (14 mg), and zinc powder (3.4 mg) were added to DMF (3 ml), and the mixture was heated at 95° C. for 3 hours. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture and subjected to celite filtration. Extraction with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=93:7). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound (1.35 g) as a white powder.

mp: 113.5-117.5° C.

Example 330 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride

To a solution of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridine 3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dion e (0.5 g), 1-methyl-3-indoleacetic acid (0.27 g), and 1-hydroxybenzotriazole (HOBT)(0.24 g) in acetonitrile (10 ml), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC) (0.30 g) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1.1 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.26 g) as a pale orange white amorphous.

¹H NMR (DMSO-d₆), δppm: 0.65 and 0.69 (3H, s), 0.95-1.13 (3H, m), 1.31 and 1.32 (3H, s), 2.90-3.05 (2H, m), 3.06 and 3.14 (3H, s), 3.20-3.90 (5H, m), 3.70 and 3.73 (3H, s), 3.90-4.08 (1H, m), 4.55-4.79 (2H, m), 6.96 (1H, t, J=7.4 Hz), 7.05-7.24 (4H, m), 7.32-7.42 (2H, m), 7.43-7.55 (1H, m), 7.63-7.79 (1H, m), 8.13 (1H, bs), 8.57-8.72 (2H, m)

Example 331 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(1-pyridin-3-ylethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 128-132° C.

Example 332

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-phenyl-N-(2-pyridin-3-ylethyl)isobutyramide hydrochloride

To a solution of 1-ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), 2-Phenylisobutyric acid (0.24 g), and diisopropylethylamine (0.23 ml) in DMF (10 ml), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.50 g) was added and stirred at 40° C. for 10 hours. Water was added to the reaction mixture, and stirred for 1 hour, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.35 g) as a white amorphous.

¹H NMR (DMSO-d₆), δppm: 0.67 and 0.72 (3H, s), 0.90-1.20 (3H, m), 1.20-1.40 (3H, m), 1.43 and 1.48 (6H, s), 2.30-2.50 (1H, m), 2.83-3.40 (5H, m), 3.40-4.30 (4H, m), 4.57-4.79 (1H, m), 6.76-7.03 (1H, m), 7.03-7.56 (8H, m), 7.56-8.80 (3H, m)

Example 333 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-3-phenyl-N-(2-pyridin-3-ylethyl)propionamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 40 using appropriate starting materials.

white amorphous

¹H NMR (DMSO-d₆), δppm: 0.70 and 0.72 (3H, s), 0.95-1.12 (3H, m), 1.33 (3H, s), 2.53-2.69 (2H, m), 2.69-2.86 (2H, m), 2.90-3.03 (2H, m), 3.25 and 3.28 (3H, s), 3.45-3.68 (2H, m), 3.69-3.81 (1H, m), 3.96-4.10 (1H, m), 4.53-4.69 (2H, m), 7.04-7.29 (7H, m), 7.43 and 7.45 (1H, d, J=4.9 Hz), 7.78-7.86 (1H, m), 8.10-8.27 (1H, m), 8.57-8.77 (2H, m)

Example 334

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)-2-quinolin-6-ylacetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.

white amorphous

¹H NMR (DMSO-d₆), δppm: 0.68 and 0.70 (3H, s), 1.00-1.08 (3H, m), 1.31 and 1.32 (3H, s), 3.03 (1H, t, J=7.0 Hz), 3.10-3.18 (1H, m), 3.23 and 3.26 (3H, s), 3.40-3.90 (2H, m), 3.95-4.13 (4H, m), 4.60-4.88 (2H, m), 7.18-7.29 (2H, m), 7.42-7.52 (1H, m), 7.66-8.04 (4H, m), 8.07-8.21 (1H, m), 8.28-8.45 (1H, m), 8.65-8.93 (3H, m), 9.06-9.16 (1H, m)

Example 335 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.

white powder

¹H NMR (DMSO-d₆), δppm: 0.71 and 0.76 (3H, s), 1.00-1.13 (3H, m), 1.33 and 1.34 (3H, s), 2.98 (1H, t, J=7.2 Hz), 3.10-3.17 (1H, m), 3.29 and 3.33 (3H, s), 3.50-3.68 (1H, m), 3.68-3.84 (2H, m), 3.97-4.13 (1H, m), 4.55-4.72 (2H, m), 4.76-4.87 (2H, m), 6.63-7.05 (4H, m), 7.15-7.38 (2H, m) 7.41-7.60 (1H, m), 7.75-7.88 (1H, m), 8.17-8.38 (1H, m), 8.56-8.86 (2H, m), 10.84 and 10.89 (1H, s)

Example 336 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]N-(pyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 124-127° C.

Example 337 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(3-methyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride (0.26 g), cesium carbonate (0.43 g), and methyl iodide (0.04 ml) were added to DMF (5 ml), and the mixture was stirred at room temperature for 1 days. Water was added to the reaction mixture, and stirred for 1 hour, followed by extraction with ethyl acetate. The organic layer was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=85:15). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (0.44 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.20 g) as a white powder.

¹H NMR (DMSO-d₆), δppm: 0.71 and 0.76 (3H, s), 1.00-1.13 (3H, m), 1.33 and 1.34 (3H, s), 2.92-3.03 (1H, m), 3.10-3.25 (1H, m), 3.30 and 3.30 (3H, s), 3.30-3.50 (3H, m), 3.50-3.81 (3H, m), 3.97-4.14 (1H, m), 4.57-4.91 (4H, m), 6.74-7.11 (3H, m), 7.11-7.40 (3H, m), 7.46 and 7.57 (1H, d, J=8.3 Hz), 7.72-7.85 (1H, m), 8.15-8.37 (1H, m), 8.63-8.86 (2H, m)

Example 338 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]benzamide

The synthesis of the title compound was performed in the same manner as in Example 42 using appropriate starting materials.

white powder

¹H NMR (CDCl₃), δppm: 0.79 (3H, bs), 1.15-1.24 (3H, m), 1.52 and 1.54 (3H, s), 2.43 (3H, d, J=0.4 Hz), 3.33-3.42 (3H, m), 3.45-3.83 (3H, m), 3.83-5.04 (5H, m), 6.27-6.77 (2H, m), 6.80-7.14 (2H, m), 7.17-7.44 (7H, m)

Example 339 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(4-methylindol-1-yl)-N-(2-pyridin-3-ylethyl)acetamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.

white powder

¹H NMR (DMSO-d₆), δppm: 0.71 and 0.77 (3H, s), 0.90-1.15 (3H, m), 1.33 and 1.35 (3H, s), 2.44 and 2.46 (3H, s), 2.89-3.13 (2H, m), 3.29 and 3.30 (3H, s), 3.58-3.65 (1H, m), 3.66-3.86 (2H, m), 3.96-4.14 (1H, m), 4.56-4.89 (2H, m), 5.10 and 5.20 (2H, s), 6.38-6.50 (1H, m), 6.77-7.03 (3H, m), 7.15-7.36 (3H, m), 7.46 and 7.57 (1H, d, J=8.3 Hz), 7.66-7.78 (1H, m), 8.09-8.23 (1H, m), 8.60-8.79 (2H, m)

Example 340 7-({N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methoxymethylpyridin-3-ylmethyl)amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder (Ether)

mp: 103-104° C.

Example 341 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 119-122° C.

Example 342 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(5-methylthiazol-4-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 144-145° C.

Example 343 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indol-3-yl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]acetamide

The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.

white amorphous

¹H NMR (CDCl₃), δppm: 0.74 and 0.78 (3H, s), 1.15-1.24 (3H, m), 1.49 and 1.51 (3H, s), 2.41 (3H, d, J=0.6 Hz), 3.11 and 3.24 (3H, s), 3.60-3.94 (9H, m), 3.94-4.26 (2H, m), 4.33-4.78 (2H, m), 6.09-6.59 (2H, m), 6.77-6.90 (1H, m), 6.90-6.98 (1H, m), 7.03-7.37 (5H, m), 7.57 (1H, d, J=8.0 Hz), 7.66 (1H, d, J=8.0 Hz)

Example 344 7-({N-(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 138-139° C.

Example 345

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)-2-quinolin-3-ylacetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.

white powder

mp: 189-194° C.

Example 346 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carboxylic acid-N-benzyl-N-(2-pyridin-3-yl-ethyl)amide

The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.

white powder

mp: 181-182° C.

Example 347 1-Ethyl-3,3,5-trimethyl-7-({N-(5-methyloxazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 129.0-130.5° C.

Example 348 1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carboxylic acid-N-(4-methoxybenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amide

The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.

white powder (Et₂O-EtOH)

mp: 151.1-155.1° C.

Example 349 7-({N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(1,5-dimethyl-1H-pyrazol-3-ylmethyl)amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 113-116° C.

Example 350

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-methylbenzoimidazol-1-yl)-N-(2-pyridin-3-yl-ethyl)acetamide

The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.

white amorphous

¹H NMR (CDCl₃), δppm: 0.82 and 0.87 (3H, s), 1.15-1.30 (3H, m), 1.53 and 1.55 (3H, s), 2.41 and 2.47 (3H, s), 2.87-3.01 (2H, m), 3.33 and 3.39 (3H, s), 3.60-3.94 (3H, m), 4.05-4.26 (1H, m), 4.50-4.87 (4H, m), 6.89 (1H, t, J=8.0 Hz), 6.98-7.60 (7H, m), 7.68 (1H, t, J=9.1 Hz), 8.44 (1H, s), 8.52 and 8.61 (1H, d, J=3.5 Hz)

Example 351 1-Ethyl-3,3,5-trimethyl-7-({[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-(3-methylpyridin-2-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder (AcOEt-Et₂O)

mp: 139-143° C.

Example 352 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.69 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.31 (3H, s), 2.80-3.20 (2H, m), 3.29 (3H, s), 3.30 (3H, s), 3.39-3.45 (2H, m), 3.70-3.77 (1H, m), 3.92-4.04 (3H, m), 4.36 (2H, br), 4.74 (2H, br), 6.76 (1H, d, J=6.9 Hz), 7.30-7.40 (3H, m), 7.59 (1H, br), 7.83 (2H, br), 8.07 (1H, d, J=5.2 Hz), 8.65 (2H, br).

Example 353 7-({N-(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white powder

¹H NMR (DMSO-d₆), δppm: 0.72 (3H, s), 1.08 (3H, t, J=7.1 Hz), 1.34 (3H, s), 2.24 (3H, s), 3.30-3.43 (5H, m), 3.73 (3H, s), 3.66-3.86 (3H, m), 3.97-4.06 (1H, m), 4.27 (2H, br), 4.43 (2H, br), 6.32-6.35 (1H, m), 6.85 (1H, d, J=7.4 Hz), 6.97 (1H, s), 7.54-7.57 (1H, m), 7.61-7.72 (2H, m), 7.87 (1H, br), 7.94-7.95 (1H, m).

Example 354 1-Ethyl-7-({N-(6-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white powder

¹H NMR (DMSO-d₆), δppm: 0.67 (3H, s), 1.04 (3H, t, J=7.0 Hz), 1.33 (3H, s), 2.40 (3H, s), 2.70-3.10 (2H, m), 3.27 (5H, br), 3.41 (3H, s), 3.65-4.10 (6H, m), 4.63 (2H, br), 6.51 (1H, br), 6.70 (1H, br), 7.57 (1H, d, J=7.2 Hz), 7.00-7.70 (4H, m), 8.23 (1H, br), 8.74 (1H, m).

Example 355 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)-N-(2-pyridin-3-ylethyl)isobutyramide

The synthesis of the title compound was performed in the same manner as in Example 332 using appropriate starting materials.

pale brown white amorphous

¹H NMR (CDCl₃), δppm: 0.74 and 0.80 (3H, s), 1.08-1.23 (3H, m), 1.50 and 1.52 (3H, s), 1.95-2.07 (6H, m), 2.15-2.35 (1H, m), 2.87 (1H, t, J=7.5 Hz), 3.16 and 3.37 (3H, s), 3.42-3.63 (2H, m), 3.63-3.88 (1H, m), 3.95-4.18 (1H, m), 4.43-4.82 (2H, m), 6.52-6.62 (1H, m), 6.80-7.32 (7H, m), 7.48 (1H, d, J=7.8 Hz), 7.99 and 8.10 (1H, s), 8.30-8.63 (2H, m)

Example 356 1-Ethyl-3,3,5-trimethyl-7-({N-[1-(2-methylpyridin-3-yl)ethyl]-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder (Ether)

mp: 164-167° C.

Example 357 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-[1-(2-methylpyridin-3-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 163-164° C.

Example 358 7-({N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-[1-(2-methylpyridin-3-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 169-170° C.

Example 359 7-({N-(2-Ethoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 104-106° C.

Example 360 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)-N-(quinolin-5-yl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

1-Ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.45 g), 5-bromoquinoline (0.25 g), tris(dibenzylideneacetone)dipalladium (5.4 mg), xantphos (10 mg), and cesium carbonate (0.46 g) were added to toluene (9 ml), and the mixture was heated at 130° C. for 3 days. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, and stirred for 1 hour, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=85:15). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1 ml) was added to a ethanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.20 g) as a yellow amorphous.

¹H NMR (DMSO-d₆), δppm: 0.55 (3H, s), 0.99 (3H, t, J=7.0 Hz), 1.29 (3H, s), 3.03 (2H, t, J=7.1 Hz), 3.14 (3H, s), 3.30-3.80 (3H, m), 3.90-4.03 (1H, m), 4.49 (2H, s), 7.06-7.20 (2H, m), 7.33 (1H, d, J=8.1 Hz), 7.49 (1H, d, J=5.4 Hz), 7.73 (1H, dd, J=4.8 Hz, 8.8 Hz), 7.78-7.90 (3H, m), 8.23 (1H, d, J=8.1 Hz), 8.64 (1H, s), 8.69 (1H, d, J=4.8 Hz), 8.73 (1H, d, J=8.8 Hz), 9.07 (1H, d, J=3.6 Hz),

Example 361

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-yl ethyl)acetamide

The synthesis of the title compound was performed in the same manner as in Example 330 using appropriate starting materials.

yellow amorphous

¹H NMR (CDCl₃), δppm: 0.70 and 0.79 (3H, s), 1.08-1.23 (3H, m), 1.49 and 1.52 (3H, s), 2.77 (1H, t, J=7.7 Hz), 2.85 (1H, t, J=7.3 Hz), 3.06 and 3.21 (3H, s), 3.52-3.82 (3H, m), 4.01-4.16 (3H, m), 4.50-4.70 (2H, m), 6.75-7.32 (5H, m), 7.32-7.50 (3H, m), 7.82-7.92 (1H, m), 8.27-8.55 (2H, m), 10.1 and 10.1 (1H, bs)

Example 362 7-({N-(4-Chloropyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 114-118° C.

Example 363 N-[3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-ylmethyl]formamide

3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbonitrile (0.40 g) and Raney nickel (1.2 g) were suspended in formic acid (8 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=75:25→80:20). The purified product was condensed under reduced pressure. Acetone and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (33 mg) as a pale brown white amorphous.

¹H NMR (CDCl₃), δppm: 0.77 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.43 (3H, d, J=0.9 Hz), 2.85 (2H, t, J=5.8 Hz), 3.35 (3H, s), 3.58-3.84 (5H, m), 4.00-4.18 (3H, m), 4.54 (2H, d, J=4.4 Hz), 6.41 (1H, dd, J=0.4 Hz, 7.3 Hz), 6.47 (1H, t, J=0.8 Hz), 6.96 (1H, d, J=7.3 Hz), 7.06 (1H, dd, J=4.9, 7.7 Hz), 7.12-7.20 (3H, m), 7.38 (1H, bs), 7.55 (1H, dd, J=1.2, 7.7 Hz), 8.32 (1H, d, J=1.2 Hz), 8.36 (1H, dd, J=1.5, 4.9 Hz)

Example 364 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]N-(quinolin-5-yl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 166-168° C.

Example 365 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1-methyl-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)propionamide

Sodium hydride (55% in oil) (52 mg) was suspended in DMF (7 ml), and cooled to 0° C. in an ice water bath.

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-yl ethyl)acetamide (210 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 30 minutes followed at room temperature for 30 minutes. Methyl iodide (0.03 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=90:10). The purified product was condensed to dryness to give the title compound (20 mg) as a pale yellow white amorphous.

¹H NMR (CDCl₃), δppm: 0.75 and 0.86 (3H, s), 1.17 and 1.21 (3H, t, J=7.1 Hz), 1.51 (3H, s), 1.54 (3H, s), 2.94 (1H, t, J=7.7 Hz), 3.06 (1H, t, J=7.2 Hz), 3.40 and 3.48 (3H, s), 3.44-3.54 (2H, m), 3.68 (1H, t, J=6.7 Hz), 3.72-3.90 (1H, m), 3.95-4.22 (2H, m), 4.18 and 4.25 (3H, s), 4.70-4.84 (1H, m), 7.03-7.75 (8H, m), 8.27-8.35 (1H, m), 8.35-8.44 (1H, m), 8.51-8.64 (1H, m)

Example 366 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-pyridin-3-ylethyl)formamide

Sodium hydride (55% in oil) (52 mg) was suspended in DMF (7 ml), and cooled to 0° C. in an ice water bath.

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-yl ethyl)acetamide (210 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 30 minutes followed at room temperature for 30 minutes. Methyl iodide (0.03 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=85:15). The purified product was condensed to dryness to give the title compound (17 mg) as a pale yellow white amorphous.

pale yellow white amorphous

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.19 and 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, bs), 2.85 (2H, t, J=7.7 Hz), 3.39 and 3.39 (3H, s), 3.44-3.54 (2H, m), 3.75-3.88 (1H, m), 4.06-4.20 (1H, m), 4.27-4.65 (2H, m), 6.98-7.10 (1H, m), 7.10-7.18 (1H, m), 7.21-7.35 (2H, m), 7.41 and 7.53 (1H, dt, J=7.9, 2.0 Hz), 8.05 and 8.30 (1H, s), 8.39 and 8.41 (1H, d, J=1.8 Hz), 8.50 and 8.62 (1H, dd, J=1.8, 4.8 Hz)

Example 367 1-Ethyl-7-({N-[1-(2-methoxymethylpyridin-3-yl)ethyl]-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

white powder

¹H NMR (DMSO-d₆), δppm: 0.75 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.34 (3H, s), 1.41 (3H, s), 2.09 (3H, s), 2.57-2.84 (2H, m), 3.16 (2H, br), 3.35 (3H, s), 3.40 (3H, s), 3.62-3.70 (2H, m), 4.00-4.13 (1H, m), 4.18 (2H, br), 6.83 (1H, br), 7.09 (1H, br), 7.43-7.63 (3H, m), 7.83 (1H, br), 7.91-7.92 (1H, m), 8.40 (1H, br), 8.46 (1H, br).

Example 368 1-Ethyl-7-({N-(2-hydroxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 187-190° C.

Example 369 7-({N,N-Bis-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diaz epine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 160-165° C.

Example 370 1-Ethyl-7-({N-(5-methoxymethyl-2-methyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 169-170° C.

Example 371 1-Ethyl-7-({N-(5-methoxymethyl-2-methyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 113-115° C.

Example 372 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 184-186° C.

Example 373 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 207-210° C.

Example 374 1-Isobutyl-3,3-dimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 180-182° C.

Example 375 1-Isobutyl-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 229-231° C.

Example 376 1-(2-Methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 182-185° C.

Example 377 1-(2-Methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 188-189° C.

Example 378 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 149-151° C.

Example 379 1-(2-Methoxyethyl)-3,3-dimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 179-181° C.

Example 380 1-(2-Methoxyethyl)-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 205-206° C.

Example 381 1-Cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 189-191° C.

Example 382 1-Cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 192-194° C.

Example 383 1-Cyclopropylmethyl-3,3-dimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 138-143° C.

Example 384 1-Cyclopropylmethyl-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 220-221° C.

Example 385 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 130-131° C.

Example 386 1-Cyclopropyl-7-({N-(2-methoxymethyl-pyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 213-214° C.

Example 387 1-Cyclopropyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 182-184° C.

Example 388 1-Cyclopropyl-3,3-dimethyl-7-({[2-N-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 172-173° C.

Example 389 1-Cyclopropyl-3,3-dimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 191-193° C.

Example 390 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 149-150° C.

Examples 391 to 582

The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.

Example No. R1 MS (M + 1) 391

461 392

472 393

472 394

475 395

477 396

491 397

478 398

489 399

487 400

461 401

564 402

540 403

489 404

492 405

529 406

506 407

492 408

505 409

492 410

486 411

486 412

486 413

486 414

486 415

490 416

475 417

506 418

489 419

475 420

486 421

490 422

540 423

502 424

478 425

478 426

473 427

462 428

473 429

486 430

502 431

476 432

486 433

462 434

462 435

476 436

560 437

487 438

500

Example No. R1 MS (M + 1) 439

517 440

528 441

528 442

531 443

533 444

547 445

534 446

545 447

543 448

517 449

620 450

596 451

545 452

548 453

585 454

562 455

548 456

561 457

548 458

542 459

542 460

542 461

542 462

542 463

546 464

531 465

562 466

545 467

531 468

542 469

546 470

596 471

558 472

534 473

534 474

529 475

518 476

529 477

542 478

558 479

532 480

542 481

518 482

518 483

532 484

616 485

543 486

556

Example No. R1 MS (M + 1) 487

527 488

538 489

538 490

541 491

543 492

557 493

544 494

555 495

553 496

527 497

630 498

606 499

555 500

558 501

595 502

572 503

558 504

571 505

558 506

552 507

552 508

552 509

552 510

552 511

556 512

541 513

572 514

555 515

541 516

552 517

556 518

606 519

568 520

544 521

544 522

539 523

528 524

539 525

552 526

568 527

542 528

552 529

528 530

528 531

542 532

626 533

553 534

566

Example No. R1 MS (M + 1) 535

517 536

528 537

528 538

531 539

533 540

547 541

534 542

545 543

543 544

517 545

620 546

596 547

545 548

548 549

585 550

562 551

548 552

561 553

548 554

542 555

542 556

542 557

542 558

542 559

546 560

531 561

562 562

545 563

531 564

542 565

546 566

596 567

558 568

534 569

534 570

529 571

518 572

529 573

542 574

558 575

532 576

542 577

518 578

518 579

532 580

616 581

543 582

556

Example 583 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyrimidin-5-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 146.2-148.2° C.

Example 584 1-Ethyl-3,3,5-trimethyl-7-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)piperidin-1-ylmethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.203 g) and acetic acid (0.063 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.170 g), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.235 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10). The purified product was condensed to dryness to give the title compound (0.205 g) as pale yellow amorphous.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.54 (3H, s), 1.68-1.75 (2H, m), 2.13-2.21 (2H, m), 2.55-2.60 (2H, m), 2.64-2.76 (2H, m), 2.80-2.85 (2H, m), 2.95-3.03 (2H, m), 3.44 (3H, s), 3.57 (2H, s), 3.77-3.85 (1H, m), 4.10-4.19 (1H, m), 4.25-4.33 (1H, m), 7.01 (1H, dt, J=1.9, 7.4 Hz), 7.14-7.28 (6H, m)

Example 585 1-Ethyl-3,3,5-trimethyl-7-[4-(2-oxo-2H-quinolin-1-yl)-piperidin-1-ylmethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.85 (3H, s), 1.21 (3H, t, J=7.0 Hz), 1.54 (3H, s), 1.70-1.77 (2H, m), 2.28-2.34 (2H, m), 2.94 (2H, br), 3.05-3.13 (2H, m), 3.46 (3H, s), 3.64 (2H, s), 3.78-3.87 (1H, m), 4.11-4.19 (1H, m), 5.33 (1H, bs), 6.67 (1H, d, J=9.4 Hz), 7.21 (1H, t, J=8.0 Hz), 7.27-7.32 (3H, m), 7.50-7.57 (2H, m), 7.62 (1H, d, J=9.4 Hz), 7.78 (1H, br)

Example 586

N-[1-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)piperidin-4-yl]-N-phenylbenzamide

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.55-1.63 (2H, m), 1.88-1.95 (2H, m), 2.16-2.26 (2H, m), 2.88-2.94 (2H, m), 3.38 (3H, s), 3.45-3.53 (2H, m), 3.73-3.82 (1H, m), 4.10-4.16 (1H, m), 4.70-4.82 (1H, m), 6.98-7.02 (2H, m), 7.07-7.24 (11H, m)

Example 587 1-Ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-pyrrolidin-1-ylmethyl]-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.73-0.82 (3H, m), 1.16-1.20 (3H, m), 1.51-1.53 (3H, m), 2.10-2.35 (2H, m), 2.55-3.20 (8H, m), 3.40-3.44 (3H, m), 3.61-4.16 (4H, m), 5.30-5.45 (1H, m), 6.98-7.04 (1H, m), 7.14-7.30 (5H, m), 7.65-7.68 (1H, m)

Example 588 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.80 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.48 (3H, s), 2.62-2.65 (2H, m), 2.94-2.98 (2H, m), 3.39 (3H, s), 3.46-3.59 (6H, m), 3.76-3.82 (1H, m), 4.09-4.13 (1H, m), 6.71 (1H, d, J=8.0 Hz), 7.09-7.17 (4H, m), 7.21-7.24 (2H, m), 7.68 (1H, dd, J=1.6, 7.7 Hz), 7.91 (1H, br), 8.38 (1H, dd, J=1.7, 4.9 Hz)

Example 589 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-methylpyridin-3-ylmethyl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.80 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.50 (3H, s), 2.62-2.65 (2H, m), 2.94-2.97 (2H, m), 3.39 (3H, s), 3.49-3.61 (6H, m), 3.76-3.84 (1H, m), 4.09-4.13 (1H, m), 6.74 (1H, d, J=1.1 Hz), 6.97 (1H, dd, J=1.4, 7.7 Hz), 7.10-7.13 (2H, m), 7.16 (1H, d, J=1.1 Hz), 7.22-7.28 (2H, m), 7.70 (1H, dd, J=1.6, 7.7 Hz), 8.17 (1H, br), 8.38 (1H, dd, J=1.6, 4.9 Hz)

Example 590 7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.205 g) was added to a methanol solution (10 ml) of 7-(aminomethyl)-1-ethyl-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.213 g). The mixture was stirred at room temperature overnight. Sodium borohydride (0.022 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The liquid was then condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1). The purified product was condensed under reduced pressure to give the title compound (0.400 g) as a white amorphous.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.77-2.81 (2H, m), 2.96-3.00 (2H, m), 3.40 (3H, s), 3.73 (2H, s), 3.74-3.83 (1H, m), 3.81 (2H, s), 4.12-4.17 (1H, m), 5.17 (2H, s), 6.83 (1H, d, J=8.3 Hz), 7.05 (1H, dd, J=1.9, 8.3 Hz), 7.16 (1H, d, J=1.6 Hz), 7.19-7.25 (6H, m), 7.27-7.33 (2H, m)

Example 591 7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 590 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.53 (3H, s), 2.77-2.80 (2H, m), 2.96-3.00 (2H, m), 3.38 (3H, s), 3.67 (2H, s), 3.68 (2H, s), 3.76-3.81 (1H, m), 4.12-4.18 (1H, m), 5.20 (2H, s), 6.90-6.95 (2H, m), 7.09 (1H, dd, J=1.8, 8.4 Hz), 7.12-7.14 (2H, m), 7.17-7.24 (4H, m), 7.25-7.30 (2H, m)

Example 592 1-Cyclopropyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

ivory powder

mp: 146-148° C.

Example 593 1-(2-Methoxyethyl)-3,3,5-trimethyl-7-({N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

white powder

mp: 127-130° C.

Example 594 1-Ethyl-3,3,5-trimethyl-7-(2-phenylpiperidin-1-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.78 and 0.81 (3H, s), 1.15-1.20 (3H, m), 1.33-1.47 (1H, m), 1.51-1.53 (3H, m), 1.55-1.84 (5H, m), 1.95-2.05 (1H, m), 2.83-2.97 (2H, m), 3.12-3.17 (1H, m), 3.38 and 3.41 (3H, s), 3.70-3.85 (2H, m), 4.07-4.18 (1H, m), 7.07-7.26 (4H, m), 7.30-7.36 (2H, m), 7.40-7.45 (2H, m)

Example 595 1-Cyclopropyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

White powder

¹H NMR (DMSO-d₆), δppm: −0.27-0.01 (1H, m), 0.43-0.46 (1H, m), 0.74 (3H, s), 0.73-0.79 (1H, m), 1.05-1.34 (1H, m), 1.34 (3H, s), 2.16 (3H, s), 2.81 (2H, br), 3.21-3.28 (1H, m), 3.28 (3H, s), 3.28 (3H, s), 3.84 (4H, br), 4.15 (2H, br), 4.55 (2H, br), 6.93 (1H, s), 7.36 (2H, br), 7.43 (2H, br), 7.77 (1H, br), 7.97 (1H, d, J=2.1 Hz), 8.38 (1H, s), 8.60 (1H, br).

Example 596 1-(2-Methoxyethyl)-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

White powder

¹H NMR (DMSO-d₆), δppm: 0.71 (3H, s), 1.35 (3H, s), 2.43 (3H, s), 2.51 (3H, s), 2.80 (2H, br), 3.12 (3H, s), 3.29 (3H, s), 3.41 (2H, t, J=5.2 Hz), 3.83 (2H, br), 3.85-3.88 (2H, m), 4.00-4.60 (4H, m), 6.46 (1H, s), 6.23 (1H, s), 7.10-7.49 (4H, m), 7.71 (1H, br), 8.28 (1H, br), 8.56 (1H, br).

Example 597 7-{N-(Benzo[1,3]dioxol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]aminomethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 135.9-137.5° C.

Example 598 1-Ethyl-3,3,5-trimethyl-7-{N-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

White amorphous

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.77-2.83 (2H, m), 2.97-3.02 (2H, m), 3.41 (3H, s), 3.76-3.83 (5H, m), 4.10-4.18 (1H, m), 5.17 (2H, s), 6.86 (1H, d, J=8.2 Hz), 6.97 (1H, dt, J=1.0 and 7.4 Hz), 7.07-7.14 (2H, m), 7.17-7.29 (7H, m)

Example 599 1-Ethyl-7-({N-(1H-indol-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

¹H NMR (CDCl₃), δppm: 0.65 (3H, s), 1.08 (3H, t, J=7.1 Hz), 1.47 (3H, s), 2.48 (3H, d, J=1.0 Hz), 2.86 (2H, t, J=5.1 Hz), 3.13 (3H, s), 3.41 (2H, s), 3.61-3.72 (1H, m), 3.91-4.17 (3H, m), 4.22-4.35 (1H, m), 4.35-4.43 (1H, m), 6.24 (1H, dd, J=0.62, 7.4 Hz), 6.47 (1H, dd, J=2.0, 3.0 Hz), 6.67 (1H, d, J=0.84 Hz), 6.73-6.84 (3H, m), 6.89 (1H, d, J=1.4 Hz), 6.95-7.03 (2H, m), 7.17 (1H, t, J=2.8 Hz), 7.52-7.59 (1H, m), 10.51 (1H, s).

Example 600 7-{N-(Benzo[1,3]dioxol-5-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]aminomethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 179.7-181.8° C.

Example 601 1-Ethyl-7-({N-(1H-indol-6-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White amorphous

¹H NMR (CDCl₃), δppm: 0.76 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.44 (3H, d, J=1.0 Hz), 2.86 (2H, dt, J=2.4, 5.9 Hz), 3.31 (3H, s), 3.62-3.83 (5H, m), 3.98-4.18 (3H, m), 6.40 (1H, dd, J=0.70, 7.3 Hz), 6.48 (1H, t, J=0.88 Hz), 6.50-6.54 (1H, m), 6.95-7.11 (4H, m), 7.15 (1H, bs), 7.19 (1H, dd, J=2.5, 3.1 Hz), 7.53 (1H, d, J=8.1 Hz), 8.10 (1H, bs).

Example 602 7-({N-(1H-Benzoimidazol-5-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White amorphous

¹H NMR (CDCl₃), δppm: 0.76 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.43 (3H, d, J=0.68 Hz), 2.80-2.92 (2H, m), 3.33 (3H, s), 3.62-3.88 (5.H, m), 3.92-4.25 (3H, m), 6.40 (1H, d, J=7.4 Hz), 6.47 (1H, s), 6.82-7.25 (5H, m), 7.26-7.92 (2H, m), 8.02 (1H, s), 9.38 (1H, bs).

Example 603 1-Isobutyl-3,3-dimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ethyl acetate-hexane-diisopropyl ether)

mp: 128-130° C.

Example 604 1-Isobutyl-3,3-dimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 206-208° C.

Example 605 1-Isobutyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Pale pink powder (ethyl acetate-hexane-diisopropyl ether)

mp: 155-159° C.

Example 606 1-Ethyl-3,3,5-trimethyl-7-({N-(3-methylimidazo[1,5-a]pyridin-1-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 104.1-109.4° C.

Example 607 1-Cyclopropylmethyl-3,3-dimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Ivory powder (ethyl acetate-hexane-diisopropyl ether)

mp: 153-155° C.

Example 608 1-Cyclopropylmethyl-3,3-dimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Ivory powder (Ether)

mp: 207-210° C.

Example 609 1-Cyclopropylmethyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 139-141° C.

Example 610 1-Isobutyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Ivory powder (Ether)

mp: 151-152° C.

Example 611 1-Ethyl-3,3,5-trimethyl-7-({N-[(1-methyl-1H-benzoimidazol-2-yl)methyl]-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 126.9-132.6° C.

Example 612 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-pyrazol-1-ylbenzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White amorphous

¹H NMR (CDCl₃), δppm: 0.78 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.44 (3H, d, J=1.0 Hz), 2.86 (2H, dt, J=1.8, 5.8 Hz), 3.30 (3H, s), 363-3.84 (5H, m), 3.98-4.23 (3H, m), 6.37 (1H, dd, J=0.68, 7.3 Hz), 6.49 (1H, t, J=0.88 Hz), 6.95 (1H, d, J=7.4 Hz), 7.03-7.15 (3H, m), 7.16-7.26 (4H, m), 7.32 (1H, d, J=7.7 Hz), 7.32-7.37 (1H, m), 7.83 (1H, t, J=1.1 Hz).

Example 613 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-pyrazol-1-yl-benzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Pale yellow white powder

mp: 123-130° C.

Example 614 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]pyrazin-2-ylmethylamino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 128.7-130.7° C.

Example 615 1-Ethyl-7-({N-(imidazo[1,2-a]pyridin-2-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.76 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.43 (3H, d, J=0.72 Hz), 2.91 (2H, t, J=5.5 Hz), 3.32 (3H, s), 3.69-3.85 (3H, m), 3.85-3.95 (2H, m), 3.95-4.22 (3H, m), 6.43 (1H, dd, J=0.68, 7.3 Hz), 6.48 (1H, s), 6.76 (1H, dt, J=1.1, 6.8 Hz), 7.02-7.11 (2H, m), 7.12-7.23 (3H, m), 7.32 (1H, s), 7.53 (1H, q, J=3.2 Hz), 7.95 (1H, td, J=1.1, 6.8 Hz).

Example 616 7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl)-N-methylamino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

7-{[N-(1-Benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethyl) amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (247 mg) was dissolved in DMF (2 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 13.56 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (73.5 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (169 mg) as a white amorphous.

¹H NMR (CDCl₃), δppm: 0.80 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.04 (3H, s), 2.75-2.8 (2H, m), 2.95-3.00 (2H, m), 3.38 (3H, s), 3.40-3.44 (4H, m), 3.75-3.85 (1H, m), 4.07-4.19 (1H, m), 5.20 (2H, s), 6.92-6.96 (2H, m), 7.07-7.14 (3H, m), 7.17-7.31 (6H, m)

Example 617 1-Ethyl-7-({N-(2-hydroxybenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 166-170° C.

Example 618 1-Isobutyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ethyl acetate-hexanes)

mp: 96-100° C.

Example 619 1-Cyclopropylmethyl-8-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ethyl acetate-hexane)

mp: 95-99° C.

Example 620 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzonitrile

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 156.7-158.6° C.

Example 621 4-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde

A 2N-hydrochloric acid (5 ml) was added to an THF solution (5 ml) of 7-({N-(4-diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.52 g), and the mixture was stirred at room temperature for 1 hour. 2N-Sodium hydroxide solution (5 ml) was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. The residue was recrystallized from ethyl acetate and ether, and dried to give the title compound (0.35 g) as a white powder.

mp: 153-155° C.

Example 622 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 152-153° C.

Example 623 1-Ethyl-7-({N-(6-methoxy-2-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 143-144° C.

Example 624 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 112-114° C.

Example 625 1,3,3-Trimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-pyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Ivory powder (Ether)

mp: 117-122° C.

Example 626 1,3,3-Trimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 154-157° C.

Example 627 1-Ethyl-3,3-dimethyl-8-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 108-114° C.

Example 628 1-Ethyl-3,3-dimethyl-8-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 177-179° C.

Example 629 1-Ethyl-7-({N-(6-methoxy-2-methylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 155-156° C.

Example 630 1,3,3-Trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-pyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 176-178° C.

Example 631 1,3,3-Trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Pale pink powder (Ether)

mp: 142-144° C.

Example 632 1-Ethyl-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 213-215° C.

Example 633 1-Ethyl-3,3-dimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 197-199° C.

Example 634 1-Ethyl-3,3,5-trimethyl-7-({N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(pyridazin-4-ylmethyl)amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 137-141° C.

Example 635 1-Ethyl-3,3,5-trimethyl-7-({[N-(1-methyl-1H-indazol-3-yl)methyl]-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 96-102° C.

Example 636 1-Ethyl-3,3,5-trimethyl-7-({N-(7-methyl-1H-indazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 111-118° C.

Example 637 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]amino}propyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.70 (3H, s), 1.04 (3H, t, J=7.0 Hz), 1.32 (3H, s), 2.62-4.68 (20H, m), 6.69-8.75 (12H, m),

Example 638 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 150.9-154.7° C.

Example 639 1-Ethyl-3,3,5-trimethyl-7-{3-[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.72 (3H, s), 1.04 (3H, t, J=7.0 Hz), 1.33 (3H, s), 2.09-3.79 (18H, m), 4.65 (2H, br-s), 7.22 (1H, d, J=8.0 Hz), 7.33 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.83 (1H, t, J=6.6 Hz), 7.93-7.97 (1H, m), 8.44 (1H, d, J=7.5 Hz), 8.76-8.80 (3H, m), 8.90 (1H, s)

Example 640 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 106.4-114.6° C.

Example 641 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 128.2-130.9° C.

Example 642 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 171-173° C.

Example 643 1-Ethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 168-170° C.

Example 644 8-({N-(2-Methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 179-182° C.

Example 645 8-({N-(2-Methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 123-134° C.

Example 646 5-Cyclopropylmethyl-1-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 159-160° C.

Example 647 5-Cyclopropylmethyl-1-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 131-135° C.

Example 648 7-[2-(4-Chlorophenyl)pyrrolidin-1-ylmethyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 and 0.80 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.65-1.98 (3H, m), 2.15-2.30 (2H, m), 3.05-3.17 (2H, m), 3.35-3.45 (4H, m), 3.70-3.83 (2H, m), 4.08-4.18 (1H, m), 7.06-7.23 (3H, m), 7.27-7.32 (2H, m), 7.34-7.38 (2H, m)

Example 649 7-(3-Benzylpiperidin-1-ylmethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.77 and 0.79 (3H, s), 0.97-2.10 (5H, m), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.45-2.55 (2H, m), 2.80-2.90 (2H, m), 3.35 and 3.40 (3H, s), 3.41-3.60 (4H, m), 3.75-3.85 (1H, m), 4.10-4.20 (1H, m), 7.08-7.26 (8H, m)

Example 650 1-Ethyl-3,3,5-trimethyl-7-(2-phenylazetidin-1-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.70 and 0.71 (3H, s), 1.10-1.15 (3H, m), 1.50 (3H, s), 2.10-2.20 (1H, m), 2.32-2.40 (1H, m), 2.90-3.01 (1H, m), 3.26 and 3.32 (3H, s), 3.41-3.46 (1H, m), 3.58-3.78 (3H, m), 4.07-4.17 (2H, m), 7.07-7.21 (4H, m), 7.22-7.28 (2H, m), 7.33-7.38 (2H, m)

Example 651 1-Ethyl-3,3,5-trimethyl-7-(6-methyl-3′,4′,5′,6′-tetrahydro-2′H-[2,3′]bipyridinyl-1′-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 and 0.82 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.54-1.83 (3H, m), 1.95-2.02 (1H, m), 2.03-2.14 (1H, m), 2.18-2.26 (1H, m), 2.51 (3H, s), 2.81-2.90 (1H, m), 2.95-3.10 (2H, m), 3.41 and 3.42 (3H, s), 3.50-3.60 (2H, m), 3.75-3.85 (1H, m), 4.08-4.17 (1H, m), 6.95-6.98 (2H, m), 7.21-7.24 (3H, m), 7.45-7.50 (1H, m)

Example 652 7-(2-Benzylpyrrolidin-1-ylmethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.53-1.83 (4H, m), 2.15-2.25 (1H, m), 2.53-2.63 (1H, m), 2.68-2.76 (1H, m), 2.88-3.06 (2H, m), 3.26-3.35 (1H, m), 3.42 and 3.43 (3H, s), 3.75-3.85 (1H, m), 4.03-4.20 (2H, m), 7.17-7.30 (8H, m)

Example 653 1-Ethyl-3,3,5-trimethyl-7-[(2-phenoxypyridin-3-ylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

White amorphous

¹H NMR (CDCl₃), δppm: 0.84 (3H, s), 1.20 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.39 (3H, s), 3.75-3.85 (1H, m), 4.09-4.19 (1H, m), 4.45 (2H, d, J=5.8 Hz), 4.89 (1H, t, J=5.8 Hz), 6.80 (1H, dd, J=1.7 and 7.8 Hz), 6.85 (1H, dd, J=4.8 and 7.8 Hz), 7.13-7.23 (3H, m), 7.24-7.34 (3H, m), 7.38-7.43 (2H, m), 7.51 (1H, dd, J=1.7 and 4.8 Hz)

Example 654 7-[(1-Benzyl-1H-pyrazol-4-ylamino)methyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

Pale brown amorphous

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.0 Hz), 1.51 (3H, s), 3.36 (3H, s), 3.75-3.82 (1H, m), 4.08-4.15 (1H, m), 4.17 (2H, s), 5.18 (2H, s), 6.85 (1H, d, J=0.8 Hz), 7.15-7.20 (3H, m), 7.21-7.35 (6H, m)

Example 655 7-[(3-Benzyloxypyrazin-2-ylamino)methyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

Pale yellow amorphous

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 3.37 (3H, s), 3.75-3.83 (1H, m), 4.07-4.15 (1H, m), 4.68 (2H, d, J=6.1 Hz), 5.41 (2H, s), 5.46 (1H, t, J=6.1 Hz), 7.20-7.25 (3H, m), 7.35-7.43 (4H, m), 7.44-7.47 (2H, m), 7.61 (1H, d, J=3.2 Hz)

Example 656 1-Ethyl-3,3,5-trimethyl-7-(3-phenethylpiperidin-1-ylmethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 and 0.83 (3H, s), 0.90-1.00 (1H, m), 1.19 (3H, t, J=7.1 Hz), 1.50-1.75 (6H, m), 1.53 (3H, s), 1.80-1.88 (1H, m), 1.90-2.00 (1H, m), 2.50-2.60 (2H, m), 2.71-2.84 (2H, m), 3.40 and 3.41 (3H, s), 3.45-3.52 (2H, m), 3.75-3.85 (1H, m), 4.10-4.20 (1H, m), 7.10-7.30 (8H, m)

Example 657 1-Ethyl-3,3,5-trimethyl-7-[(4-phenoxymethylthiazol-2-ylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

White amorphous

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.39 (3H, s), 3.76-3.85 (1H, m), 4.09-4.19 (1H, m), 4.53 (2H, d, J=5.0 Hz), 5.04 (2H, s), 5.69 (1H, brs), 6.54 (1H, s), 6.95-7.00 (3H, m), 7.23-7.32 (5H, m)

Example 658 1-Ethyl-3,3,5-trimethyl-7-[2-(4-trifluoromethylphenyl)pyrrolidin-1-ylmethyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 and 0.80 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.52 (3H, s), 1.68-2.00 (3H, m), 2.20-2.32 (2H, m), 3.10-3.23 (2H, m), 3.39 (3H, s), 3.47-3.51 (1H, m), 3.70-3.82 (2H, m), 4.09-4.16 (1H, m), 7.07-7.23 (3H, m), 7.53-7.62 (4H, m)

Example 659 7-[2-(2-Chlorophenyl)pyrrolidin-1-ylmethyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 and 0.80 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.55-1.70 (1H, m), 1.75-1.95 (2H, m), 2.28-2.45 (2H, m), 3.12-3.18 (1H, m), 3.25-3.30 (1H, m), 3.39 and 3.40 (3H, s), 3.71-3.85 (2H, m), 3.92-4.00 (1H, m), 4.09-4.20 (1H, m), 7.11-7.22 (4H, m), 7.24-7.34 (2H, m), 7.73-7.78 (1H, m)

Example 660 7-[2-(3-Chlorophenyl)pyrrolidin-1-ylmethyl]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.80 (3H, s), 1.14-1.19 (3H, m), 1.52 (3H, s), 1.65-2.00 (3H, m), 2.17-2.31 (2H, m), 3.06-3.22 (2H, m), 3.35-3.44 (4H, m), 3.73-3.81 (2H, m), 4.08-4.16 (1H, m), 7.06-7.30 (6H, m), 7.43-7.47 (1H, m)

Example 661 5-Cyclopropylmethyl-1-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (diisopropyl ether)

mp: 127-128° C.

Example 662 1-Cyclopropylmethyl-5-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 131° C.

Example 663 1-Cyclopropylmethyl-5-(2-methoxyethyl)-3,3-dimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (Ether)

mp: 146-148° C.

Example 664 1-Cyclopropylmethyl-5-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ether)

mp: 128-129° C.

Example 665 Acetic Acid 3-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-ylmethyl ester

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.78 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.09 (3H, s), 2.43 (1H, d, J=0.96 Hz), 2.84 (2H, t, J=6.4 Hz), 3.35 (3H, s), 3.66-3.80 (5H m), 4.02-4.15 (3H, m), 5.16 (2H, s), 6.40 (1H, d, J=7.3 Hz), 6.50 (1H, br), 6.88 (1H, d, J=7.3 Hz), 7.07-7.19 (4H, m), 7.58 (1H, dd, J=7.8, 1.6 Hz), 8.46 (1H, dd, J=4.8, 1.6 Hz).

Example 666 1-Ethyl-7-({N-(2-hydroxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Potassium carbonate (2.0 g) was added to a methanol solution (30 mL) of (3-((((1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl)(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)pyridin-2-yl)methyl acetate (3.0 g) and the mixture was stirred overnight at room temperature. The resulting mixture was filtered and evaporated. The residue was purified by column-chromatography (methanol:ethyl acetate=0:100→1:9) to give the titled compound as ivory powder (1.95 g).

mp: 186-188° C.

Example 667 5-Cyclopropyl-1-cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder (ethyl acetate-hexane)

mp: 121-122° C.

Example 668 1-Ethyl-3,3,5-trimethyl-7-{3-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 134.7-134.8° C.

Example 669 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbaldehyde

2-iodoxybenzoic acid (IBX, 0.235 g) was added to the dimethyl sulfoxide suspension (10 mL) of 1-ethyl-7-((N-((2-(hydroxymethyl)pyridin-3-yl)methyl)-N-(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.48 g) and the mixture was stirred overnight at room temperature. Water was added to the resulting mixture and then the mixture was extracted with ethyl acetate twice. The combined organic layer was concentrated under reduced pressure, and then the residue was purified by column-chromatography (ethyl acetate:hexanes=50:50→100:0). The purified product was recrystallized from ether to afford the titled compound as ivory powder (0.29 g).

mp: 147-149° C.

Example 670 1-Ethyl-3,3,5-trimethyl-7-{[(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Trifluoroacetic acid (43.2 mg) was added to a dichloromethane solution (5 ml) of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)carbamic acid tert-butyl ester (208 mg), and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane, and condensed under reduced pressure to give the title compound (148 mg) as a white amorphous.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.62-2.67 (2H, m), 2.86-2.93 (2H, m), 3.37 (3H, s), 3.42 (3H, s), 3.75-3.86 (5H, m), 4.10-4.17 (1H, m), 6.97-7.02 (2H, m), 7.12-7.15 (1H, m), 7.22-7.29 (3H, m)

Example 671 1-Ethyl-3,3,5-trimethyl-7-{[(2-oxo-1-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.80 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.75-2.81 (2H, m), 2.95-3.02 (2H, m), 3.38 (3H, s), 3.69-3.73 (4H, m), 3.75-3.83 (1H, m), 4.09-4.16 (1H, m), 5.20 (2H, s), 6.78 (1H, brs), 6.96 (1H, dd, J=1.2 and 7.6 Hz), 7.08 (1H, dd, J=1.9 and 8.4 Hz), 7.11-7.18 (4H, m), 7.23 (1H, d, J=8.4 Hz), 8.50-8.53 (2H, m)

Example 672 7-({N-(3-Aminopyridin-2-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

Ivory powder

mp: 217-218° C.

Example 673 7-({N-(3-Aminopyridin-2-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 188-192° C.

Example 674 7-({N-(2-Diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

mp: 138-139° C.

Example 675 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde

The synthesis of the title compound was performed in the same manner as in Example 621 using appropriate starting materials.

mp: 157-158° C.

Example 676 1-Cyclopropylmethyl-5-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.00 (2H, br), 0.21-0.23 (2H, m), 0.61 (3H, s), 0.75 (1H, br), 1.26 (3H, s), 2.35 (3H, s), 2.68 (2H, br), 3.24 (3H, s), 3.12-3.80 (6H, m), 3.90-4.20 (6H, m), 4.50 (2H, s), 6.41 (1H, s), 6.55 (1H, br), 7.20 (1H, br), 7.25-7.50 (3H, m), 7.60 (1H, br), 8.20 (1H, br), 8.48 (1H, s).

Example 677 5-Cyclopropyl-1-cyclopropylmethyl-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: −0.09-0.05 (3H, m), 0.12-0.23 (2H, m), 0.35-0.46 (1H, m), 0.63-0.80 (2H, m), 0.72 (3H, s), 1.06-1.13 (1H, m), 1.33 (3H, s), 2.43 (3H, s), 2.81 (2H, br), 3.20 (1H, br), 3.34 (3H, s), 3.37-3.45 (2H, m), 3.80 (2H, br), 4.15-4.20 (3H, m), 4.67 (3H, br), 6.49 (1H, br), 6.66 (1H, br), 7.13-7.60 (4H, m), 7.77-7.80 (1H, m), 8.42 (1H, br), 8.63 (1H, br).

Example 678 7-({N-(3-Diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

mp: 112-114° C.

Example 679 3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde

The synthesis of the title compound was performed in the same manner as in Example 621 using appropriate starting materials.

mp: 79-84° C.

Example 680 1-Ethyl-7-({N-(2-hydroxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium borohydride (47 mg) were added to a methanol solution (10 ml) of 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.59 g) and the mixture was stirred for 3 hours at 0° C. Water was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was recrystallized from ethyl acetate-ether mixture to give the title compound (0.42 g) as a pale brown white powder.

mp: 159-161° C.

Example 681 1-Ethyl-3,3,5-trimethyl-7-{[4-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzylamino]-methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.76-2.81 (2H, m), 2.95-3.02 (2H, m), 3.41 (3H, s), 3.74-3.83 (5H, m), 4.10-4.18 (1H, m), 5.17 (2H, s), 6.85-6.90 (1H, m), 6.96-7.00 (1H, m), 7.07-7.13 (1H, m), 7.15-7.35 (8H, m)

Example 682 5-Cyclopropylmethyl-1-(2-methoxyethyl)-7-({N-(2-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.03-0.10 (2H, m), 0.25-0.29 (2H, m), 0.66 (3H, s), 0.77-0.85 (1H, m), 1.30 (3H, s), 2.38 (3H, s), 2.95-3.15 (2H, m), 3.07 (3H, s), 3.10-3.42 (4H, m), 3.30 (3H, s), 3.50-3.57 (1H, m), 3.87 (2H, br), 3.97-4.09 (1H, m), 4.33 (4H, br), 4.77 (2H, br), 6.48 (1H, s), 6.64 (1H, d, J=7.3 Hz), 7.47 (2H, br), 7.57-7.60 (1H, m), 7.79-7.82 (2H, m), 8.66-8.67 (2H, m).

Example 683 5-Cyclopropyl-1-cyclopropylmethyl-3,3-dimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: −0.09-0.03 (3H, m), 0.15-0.27 (2H, m), 0.37-0.44 (1H, m), 0.72 (3H, s), 0.65-0.76 (2H, m), 1.06-1.10 (1H, m), 1.33 (3H, s), 2.43 (3H, br), 2.49 (3H, br), 2.79 (2H, br), 3.17-3.22 (1H, m), 3.38-3.49 (1H, m), 3.77 (2H, br), 3.81 (2H, br), 4.14 (2H, br), 4.16-4.22 (1H, m), 6.45 (1H, s), 6.62 (1H, d, J=7.0 Hz), 7.26 (1H, br), 7.36 (1H, br), 7.45-7.48 (2H, m), 7.68-7.72 (1H, m), 8.29 (1H, br), 8.56 (1H, br).

Example 684 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-morpholin-4-ylmethylbenzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Morpholine (0.06 ml) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (7 ml) of 2-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.35 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.20 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by extraction by dichloromethane. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure.

The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=3:2). The purified product was condensed under reduced pressure to give the title compound (0.30 g) as a white amorphous solid.

¹H NMR (CDCl₃), d ppm: 0.78 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.28-2.38 (4H, m), 2.43 (3H, d, J=1.0 Hz), 2.83 (2H, t, J=6.1 Hz), 3.32 (3H, s), 3.43 (2H, s), 3.56-3.88 (9H, m), 3.96-4.07 (2H, m), 4.07-4.18 (1H, m), 6.40 (1H, dd, J=0.64, 7.4 Hz), 6.48 (1H, d, J=0.88 Hz), 6.89 (1H, d, J=7.3 Hz), 7.08 (2H, d, J=0.96 Hz), 7.12-7.20 (3H, m), 7.21-7.26 (1H, m), 7.37 (1H, dd, J=2.1, 7.0 Hz).

Example 685 1-Ethyl-7-({N-(3-hydroxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 680 using appropriate starting materials.

mp: 170-172° C.

Example 686 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-morpholin-4-ylmethylbenzyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

¹H NMR (CDCl₃) 0.77 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.37-2.46 (4H, m), 2.43 (3H, d, J=0.96 Hz), 2.82 (2H, dt, J=2.3, 5.8 Hz), 3.31 (3H, s), 3.41 (2H, s), 3.59-3.82 (9H, m), 3.96-4.19 (3.H, m), 6.44 (1H, dd, J=0.70 7.4 Hz), 6.48 (1H, t, J=0.9 Hz), 6.97-7.09 (3H, m), 7.11-7.26 (5H, m).

Example 687 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-oxo-1-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.75-2.81 (2H, m), 2.95-3.01 (2H, m), 3.39 (3H, s), 3.70-3.73 (4H, m), 3.74-3.84 (1H, m), 4.08-4.14 (1H, m), 5.30 (2H, s), 6.95 (1H, dd, J=1.3 and 7.6 Hz), 7.05 (1H, brs), 7.11-7.25 (6H, m), 7.60 (1H, dt, J=1.8 and 7.7 Hz), 8.50-8.55 (1H, m)

Example 688 1-Ethyl-3,3,5-trimethyl-7-{[N-(2-oxo-1-pyridin-3-ylmethyl-1,2,3,4-tetrahydroquinolin-7-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.75-2.80 (2H, m), 2.94-2.99 (2H, m), 3.39 (3H, s), 3.70-3.73 (4H, m), 3.75-3.84 (1H, m), 4.08-4.18 (1H, m), 5.22 (2H, s), 6.91 (1H, brs), 6.96 (1H, dd, J=1.2 and 7.6 Hz), 7.10-7.18 (3H, m), 7.20-7.24 (2H, m), 7.55 (1H, dt, J=2.2 and 7.8 Hz), 8.47 (1H, dd, J=1.6 and 4.8 Hz), 8.56 (1H, d, J=1.8 Hz)

Example 689 1-Ethyl-3,3,5-trimethyl-7-({N-methyl-N-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 616 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.15-1.21 (3H, m), 1.53 (3H, s), 2.16 (3H, s), 2.76-2.81 (2H, m), 2.95-3.01 (2H, m), 3.40 (3H, s), 3.47-3.54 (4H, m), 3.75-3.82 (1H, m), 4.08-4.16 (1H, m), 5.18 (2H, s), 6.86 (1H, dd, J=0.8 and 8.1 Hz), 6.95 (1H, dt, J=1.0 and 7.4 Hz), 7.04-7.12 (2H, m), 7.15-7.30 (7H, m)

Example 690 1-Ethyl-3,3,5-trimethyl-7-({N-methyl-N-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-benzyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 616 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.18 (3H, s), 2.76-2.81 (2H, m), 2.95-3.01 (2H, m), 3.41 (3H, s), 3.48-3.52 (4H, m), 3.75-3.82 (1H, m), 4.08-4.17 (1H, m), 5.17 (2H, s), 6.85-6.90 (1H, m), 6.95-7.00 (1H, m), 7.06-7.13 (1H, m), 7.15-7.33 (8H, m)

Example 691 7-({N-(2-Dimethylaminomethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione trihydrochloride

To the 1,2-dichloroethan suspension (5 ml) of 3-((N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl)-N-(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)picolinaldehyde (205 mg), dimethylammonium chloride (59 mg) and triethylamine (0.10 ml) was added sodium triacetoxyborohydride (114 mg) at room temperature, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and then the residue was purified by column-chromatography (methanol:ethyl acetate=1:9→50:50). The purified product was dissolved in ethyl acetate (ca. 5 mL) and then 4 M HCl/ethyl acetate was added to the mixture. The precipitate was collected and dried in vacuo to give the titled compound as light brown powder (114 mg).

¹H NMR (DMSO-d₆), δppm: 0.70 (3H, s), 1.06 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.40 (3H, br), 2.89 (6H, s), 3.15-3.44 (2H, m), 3.34 (3H, s), 3.70-4.05 (10H, m), 6.55 (1H, s), 6.73 (1H, d, J=7.4 Hz), 7.20-8.00 (5H, m), 8.26 (1H, br), 8.64 (1H, br).

Example 692 1-Ethyl-3,3,5-trimethyl-7-({N-(2-methylaminomethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

To a methanol solution (5 ml) of 3-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbaldehyde (243 mg) was added 9.8 M THF solution of methylamine (87 μl) and the mixture was stirred overnight at room temperature. NaBH₄ (16 mg) was added to the mixture, and then the mixture was stirred overnight. The resulting mixture was evaporated and the residue was purified by column chromatography (methanol:ethyl acetate=1:9→50:50). The purified product was dissolved in ethyl acetate (ca. 5 ml) and then 4 M HCl/ethyl acetate was added to the mixture. The precipitate was collected and dried in vacuo to give the titled compound as light brown powder (18 mg).

¹H NMR (DMSO-d₆), δppm: 0.70 (3H, s), 1.06 (3H, t, J=7.0 Hz), 1.34 (3H, s), 2.40 (3H, br), 2.66 (3H, s), 3.05-3.45 (2H, m), 3.34 (3H, s), 3.70-4.05 (10H, m), 6.56 (1H, s), 6.74 (1H, d, J=7.4 Hz), 7.48 (3H, br), 7.64 (1H, d, J=6.5 Hz), 7.77 (1H, br), 8.23 (1H, br), 8.62 (1H, br), 9.32 (2H, br).

Example 693 7-({N-(2-Cyclopropylaminomethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 692 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.72 (3H, s), 0.70-0.74 (2H, m), 0.98 (2H, br), 1.08 (3H, t, J=7.0 Hz), 1.35 (3H, s), 2.41 (3H, br), 2.75 (2H, br), 3.33 (3H, s), 3.60-3.90 (5H, m), 3.91-4.05 (1H, m), 4.20-4.70 (5H, m), 6.55 (1H, s), 6.73 (1H, d, J=7.3 Hz), 7.45 (3H, br), 7.59-7.61 (2H, m), 8.15 (1H, br), 8.59 (1H, br), 9.54 (2H, br).

Example 694 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-pyrrolidin-1-ylmethylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 691 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.71 (3H, s), 1.06 (3H, t, J=7.0 Hz), 1.35 (3H, s), 2.00 (4H, br), 2.43 (3H, br), 2.76 (2H, br), 3.28 (7H, br), 3.75 (4H, br), 3.90-4.30 (2H, m), 4.55 (4H, br), 6.52 (1H, br), 6.70 (1H, br), 7.25 (2H, br), 7.32 (1H, br), 7.52 (2H, br), 7.69 (1H, br), 8.47 (1H, br), 10.3 (1H, br).

Example 695 1-Ethyl-7-({N-[2-(3-hydroxypyrrolidin-1-ylmethyl)pyridin-3-ylmethyl]-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 691 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.71 (3H, s), 1.07 (3H, t, J=6.9 Hz), 1.35 (3H, s), 1.95 (1H, br), 2.19 (1H, br), 2.42 (3H, br), 2.75 (2H, br), 3.10-3.60 (9H, m), 3.75 (4H, br), 3.90-4.25 (3H, m), 4.47 (2H, br), 6.52 (1H, br), 6.70 (1H, br), 7.27 (3H, br), 7.53 (2H, br), 7.69 (1H, br), 8.49 (1H, br), 10.4 (1H, br).

Example 696 1-Ethyl-3,3,5-trimethyl-7-{[2-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzylamino]-methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.78-2.83 (2H, m), 2.99-3.04 (2H, m), 3.32 (3H, s), 3.74-3.81 (1H, m), 3.90-3.93 (4H, m), 4.08-4.14 (1H, m), 5.30-5.34 (2H, m), 6.82 (1H, dd, J=1.0 and 7.9 Hz), 6.91-7.03 (3H, m), 7.13-7.35 (7H, m)

Example 697 1-Ethyl-3,3,5-trimethyl-7-({N-(4-methylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 120-121° C.

Example 698 7-({N-(2,6-Dimethylpyridin-3-ylmethyl)-N-[2-(2-oxo-2H-quinolin-1-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 159-160° C.

Example 699 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 174-175° C.

Example 700 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 163-165° C.

Example 701 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyrimidin-5-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 166-167° C.

Example 702 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(4-methyl-7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 174-177° C.

Example 703 1-Ethyl-3,3,5-trimethyl-7-({N-methyl-N-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)benzyl]amino}methyl)-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 616 using appropriate starting materials.

White powder

mp: 125-127° C.

Example 704 1-Ethyl-7-({N-(6-hydroxymethylpyridin-3-ylmethyl)-N-[2-(1-oxo-1H-isoquinolin-2-yl)-ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using 6-((tert-butyldimethylsilyloxy)methyl)nicotinaldehyde and 1-ethyl-3,3,5-trimethyl-7-((2-(1-oxoisoquinolin-2(1H)-yl)ethylamino)methyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione, followed by deprotection of TBDMS group with tetrabutylammonium fluoride.

¹H NMR (CDCl₃), δppm: 0.75 (3H, s), 1.13 (3H, t, J=7.1 Hz), 1.50 (3H, s), 2.85-2.88 (2H, m), 3.27 (3H, s), 3.62-3.75 (5H, m), 3.96-4.02 (1H, m), 4.13 (2H, t, J=7.2 Hz), 4.65 (2H, s), 6.46 (1H, d, J=7.3 Hz), 6.93 (1H, d, J=7.3 Hz), 6.96-6.99 (2H, m), 7.05 (1H, dd, J=1.8, 8.4 Hz), 7.13 (1H, d, J=1.6 Hz), 7.48-7.57 (3H, m), 7.66-7.71 (1H, m), 8.33 (1H, dd, J=0.6, 8.1 Hz), 8.41 (1H, d, J=1.5 Hz).

Example 705 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-dd, δppm: 0.71 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.33 (3H, s), 1.65-2.34 (2H, m), 2.52-2.92 (6H, m), 3.25-4.82 (12H, m), 6.60-6.92 (1H, m), 7.03-7.19 (1H, m), 7.19-7.31 (1H, m), 7.31-7.41 (2H, m), 7.41-7.90 (2H, m), 8.00-8.11 (1H, m), 8.12-8.60 (2H, m).

Example 706 1-Ethyl-3,3,5-trimethyl-7-(3-{N-(2-methylpyridin-3-ylmethyl)-N-[2-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)ethyl]amino}propyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.71 (3H, s), 1.04 (3H, t, J=7.1 Hz), 1.32 (3H, s), 1.66-2.29 (2H, m), 2.55-2.71 (2H, m), 2.71-2.92 (4H, m), 2.96-4.81 (12H, m), 6.81-7.02 (2H, m), 7.02-7.41 (4H, m), 7.41-7.69 (1H, m), 7.41-7.90 (2H, m), 8.42-8.93 (1H, m),

Example 707 7-{[2-(2,6-Dimethylpyridin-3-yl)ethylamino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 590 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.49 (3H, s), 2.51 (3H, s), 2.78-2.83 (2H, m), 2.85-2.89 (2H, m), 3.40 (3H, s), 3.74-3.84 (1H, m), 3.84 (2H, s), 4.09-4.19 (1H, m), 6.93 (1H, d, J=7.7 Hz), 7.17-7.19 (2H, m), 7.24 (1H, s), 7.32 (1H, d, J=7.7 Hz).

Example 708 7-{[N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.23 (3H, s), 3.42 (3H, s), 3.75-3.83 (8H, m), 4.09-4.20 (1H, m), 5.94 (1H, s), 7.20-7.28 (3H, m).

Example 709 1-Ethyl-7-{[N-(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.41 (3H, s), 3.42 (3H, s), 3.74-3.85 (1H, s), 3.85 (2H, s), 3.91 (2H, s), 4.10-4.67 (1H, m), 4.67 (2H, s), 7.22-7.28 (4H, m), 7.72-7.74 (1H, m), 8.49-8.51 (1H, m).

Example 710 1-Ethyl-3,3,5-trimethyl-7-{[N-(3-methyl-3H-imidazol-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.69 (3H, s), 3.75-3.84 (1H, m), 3.80 (2H, s), 3.83 (2H, s), 4.11-4.18 (1H, m), 6.92 (1H, s), 7.20-7.23 (2H, m), 7.25-7.28 (1H, m), 7.42 (1H, s).

Example 711 1-Ethyl-3,3,5-trimethyl-7-[(1-pyridin-3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81-0.82 (3H, m), 1.17 (3H, t, J=7.1 Hz), 1.42-1.44 (3H, m), 1.53 (3H, s), 3.40-3.41 (3H, m), 3.62-3.70 (2H, m), 3.73-3.83 (1H, m), 3.85-3.91 (1H, m), 4.09-4.19 (1H, m), 7.14-7.19 (2H, m), 7.22-7.31 (2H, m), 7.70-7.74 (1H, m), 8.51-8.53 (1H, m), 8.58 (1H, d, J=2.0 Hz).

Example 712 7-{[(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.77 (6H, s), 2.26 (3H, s), 3.42 (3H, s), 3.74-3.85 (1H, m), 3.74 (3H, s), 3.77 (2H, s), 3.86 (2H, s), 5.96 (1H, s), 7.23-7.24 (3H, m).

Example 713 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-nitrobenzenesulfonamide

Triethylamine (0.6 ml) was added to a dichloromethane solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-aminomethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.0 g). The mixture was cooled with ice.

2-Nitrobenzenesulphonyl chloride (0.80 g) was added, and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane.

The organic layer was washed with water and saturated saline, dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:4). The purified product was condensed under reduced pressure, and the residue was recrystallized from the ethyl acetate-hexane mixture to give the title compound (1.38 g) as a white solid.

¹H NMR (CDCl₃), δppm: 0.78 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 3.35 (3H, s), 3.72-3.83 (1H, m), 4.06-4.17 (1H, m), 4.35 (2H, d, J=6.4 Hz), 5.78 (1H, d, J=6.4 Hz), 7.16-7.23 (3H, m), 7.73-7.79 (2H, m), 7.86-7.91 (1H, m), 8.12-8.15 (1H, m)

Example 714 1-Ethyl-3,3,5-trimethyl-7-{[(5-methyloxazol-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.29 (3H, s), 3.42 (3H, s), 3.68 (2H, s), 3.72-3.86 (3H, m), 4.09-4.23 (1H, m), 7.20-7.30 (3H, m), 7.74 (1H, s).

Example 715 1-Ethyl-7-{[(6-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.49 (3H, s), 3.74-3.85 (1H, m), 3.83 (2H, s), 3.85 (2H, s), 4.10-4.20 (1H, m), 4.58 (2H, s), 7.23-7.37 (3H, m), 7.40 (1H, d, J=8.0 Hz), 7.71 (1H, dd, J=8.0, 2.1 Hz), 8.53 (1H, d, J=1.9 Hz).

Example 716 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methyl-1-oxypyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

To a dichloromethane solution (10 ml) of 1-ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.0 g) was added m-chloroperbenzoic acid (mCPBA, 0.89 g) at 0° C. and the mixture was stirred overnight. The resulting mixture was charged on silica gel and purified by column chromatography (methanol/ethyl acetate 1:9→1:1) to give the titled compound as white amorphous (0.46 g).

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.35 (3H, s), 2.44 (3H, d, J=1.0 Hz), 2.84 (2H, t, J=6.1 Hz), 3.35 (3H, s), 3.62 (2H, s), 3.69-3.83 (3H, m), 4.03-4.18 (3H, m), 6.41 (1H, dd, J=7.3, 0.7 Hz), 6.51 (1H, t, J=0.9 Hz), 6.85 (1H, d, J=7.3 Hz), 6.92-6.96 (1H, m), 7.09-7.11 (2H, m), 7.15-7.18 (1H, m), 7.21-7.22 (1H, m), 8.14 (1H, d, J=6.0 Hz).

Example 717 1-Ethyl-3,3,5-trimethyl-7-{[(3-methyl-pyridin-2-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.28 (3H, s), 3.42 (3H, s), 3.73-3.87 (1H, m), 3.91 (2H, s), 3.93 (2H, s), 4.08-4.23 (1H, m), 7.11 (1H, dd, J=4.8, 7.6 Hz), 7.22-7.34 (3H, m), 7.41-7.47 (1H, m), 8.41 (1H, dd, J=1.1, 4.8 Hz).

Example 718 1-Ethyl-3,3,5-trimethyl-7-{[1-(2-methylpyridin-3-yl)ethylamino]-methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82-0.83 (3H, m), 1.15-1.89 (3H, m), 1.35-1.37 (3H, m), 1.53 (3H, s), 2.52 (3H, d, J=8.0 Hz), 3.39-3.40 (3H, m), 3.66 (2H, s), 3.73-3.82 (1H, m), 4.05-4.20 (2H, m), 7.18-7.20 (3H, m), 7.23-7.24 (1H, m), 7.85 (1H, dd, J=7.8, 1.6 Hz), 8.40 (1H, d, J=4.7 Hz).

Example 719 7-{[(2-Ethoxymethylpyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.17 (6H, t, J=7.0 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.57 (2H, q, J=7.0 Hz), 3.74-3.83 (1H, m), 3.84 (2H, s), 3.92 (2H, s), 4.09-4.20 (1H, m), 4.71 (2H, s), 7.22-7.28 (4H, m), 7.71 (1H, dd, J=7.7, 1.6 Hz), 8.49 (1H, dd, J=4.8, 1.6 Hz).

Example 720 1-Ethyl-7-{[1-(2-methoxymethylpyridin-3-yl)ethylamino]methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 584 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82-0.83 (3H, m), 1.16 (3H, t, J=6.9 Hz), 1.40 (3H, d, J=6.4 Hz), 1.52 (3H, s), 3.37-3.40 (6H, m), 3.60 (1H, d, J=13.6 Hz), 3.68 (1H, d, J=13.6 Hz), 3.72-3.82 (1H, m), 4.09-4.20 (1H, m), 4.23-4.30 (1H, m), 4.57-4.66 (2H, m), 7.15-7.19 (2H, m), 7.22-7.26 (1H, m), 7.27-7.32 (1H, m), 7.96-7.98 (1H, m), 8.49 (1H, dd, J=4.7, 1.7 Hz).

Example 721 1-Ethyl-3,3,5-trimethyl-7-{[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

2-(2-Aminoethyl)-2H-isoquinolin-1-one (1.0 g) was added to a methanol solution (15 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (1.46 g). The mixture was stirred for 0.5 hours at room temperature. Sodium borohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→8:2). The purified product was condensed under reduced pressure to give the title compound (1.92 g) as a white solid.

¹H NMR (CDCl₃), δppm: 0.78 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.51 (3H, s), 3.01-3.11 (2H, m), 3.31 (3H, s), 3.71-3.81 (1H, m), 3.84 (2H, s), 4.04-4.15 (1H, m), 4.16 (2H, t, J=6.0 Hz), 6.51 (1H, d, J=7.3 Hz), 7.12-7.18 (4H, m), 7.48-7.56 (2H, m), 7.63-7.70 (1H, m), 8.41 (1H, d, J=8.1 Hz)

Example 722 1-Ethyl-3,3,5-trimethyl-7-(quinolin-5-ylaminomethyl)-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.86 (3H, s), 1.21 (3H, t, J=7.1 Hz), 1.54 (3H, s), 3.38 (3H, s), 3.76-3.89 (1H, m), 4.09-4.22 (1H, m), 4.56 (2H, d, J=4.4 Hz), 4.70-4.88 (1H, m), 6.62 (1H, dd, J=2.6, 6.1 Hz), 7.28-7.35 (3H, m), 7.38 (1H, dd, J=4.2, 8.6 Hz), 7.50-7.58 (2H, m), 8.23 (1H, dd, J=1.4, 8.6 Hz), 8.92 (1H, dd, J=1.6, 4.2 Hz).

Example 723 7-{[(4-Chloro-pyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.72-3.90 (3H, m), 3.96 (2H, s), 4.08-4.22 (1H, m), 7.22-7.27 (3H, m), 7.33 (1H, d, J=5.3 Hz), 8.44 (1H, d, J=5.3 Hz), 8.60 (1H, s).

Example 724 7-{[(2-Chloropyridin-3-ylmethyl)amino]methyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.84 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.74-3.86 (1H, m), 3.86 (2H, s), 3.93 (2H, s), 4.08-4.23 (1H, m), 7.21-7.31 (4H, m), 7.80 (1H, dd, J=1.9, 7.5 Hz), 8.32 (1H, dd, J=1.9, 4.8 Hz).

Example 725 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-pyridin-3-ylmethyl)carbamic acid tert-butyl ester

To a THF solution (15 ml) of 1-ethyl-3,3,5-trimethyl-7-(((2-methylpyridin-3-yl)methylamino)methyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.92 g) was added di-tert-butyl dicarbonate (0.58 g) at room temperature, the mixture was stirred overnight. The resulting mixture was concentrated and then purified by column chromatography (ethyl acetate/hexanes 1:4→1:1→7:3) to give the titled compound as colorless oil (0.88 g).

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.49 (9H, s), 1.53 (3H, s), 2.45 (3H, s), 3.36 (3H, s), 3.75-3.84 (1H, m), 4.09-4.18 (1H, s), 4.43 (4H, br), 6.99-7.12 (3H, m), 7.23-7.25 (1H, m), 7.35-7.38 (1H, m), 8.39-8.41 (1H, m).

Example 726 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(4-methylthiazol-5-ylmethyl)carbamic acid tert-butyl ester

The synthesis of the title compound was performed in the same manner as in Example 725 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.45-1.55 (12H, m), 2.34 (3H, s), 3.36 (3H, s), 3.76-3.84 (1H, m), 4.09-4.16 (1H, m), 4.42 (2H, s), 4.54 (2H, s), 7.00-7.09 (2H, m), 7.24-7.27 (1H, m), 8.62 (1H, s).

Example 727 N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)carbamic acid tert-butyl ester

The synthesis of the title compound was performed in the same manner as in Example 725 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.49 (9H, br), 1.54 (3H, s), 2.21 (3H, s), 3.38 (3H, s), 3.72 (3H, br), 3.75-3.85 (1H, m), 4.09-4.18 (1H, m), 4.35 (2H, br), 4.44 (2H, br), 5.88 (1H, s), 7.00-7.05 (2H, m), 7.24-7.27 (1H, m).

Example 728 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-1-oxypyridin-3-ylmethyl)carbamic acid tert-butyl ester

The synthesis of the title compound was performed in the same manner as in Example 716 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.20 (3H, t, J=7.0 Hz), 1.49 (9H, s), 1.54 (3H, s), 2.45 (3H, s), 3.38 (3H, s), 3.76-3.86 (1H, m), 4.08-4.16 (1H, m), 4.43 (4H, br), 6.99-7.12 (4H, m), 7.25-7.29 (1H, m), 8.21-8.23 (1H, m).

Example 729 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-hydroxymethylpyridin-3-ylmethyl)carbamic acid tert-butyl ester

The synthesis of the title compound was performed in the same manner as in Example 666 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.13 (3H, t, J=7.1 Hz), 1.49 (9H, br), 1.53 (3H, s), 3.36 (3H, s), 3.75-3.84 (1H, m), 4.07-4.18 (1H, m), 4.40 (4H, br), 4.62 (2H, s), 7.00-7.08 (2H, m), 7.24-7.27 (2H, m), 7.47-7.49 (1H, m), 8.47-8.49 (1H, m).

Example 730 1-Ethyl-3,3,5-trimethyl-7-{[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethylamino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 3.00-3.10 (2H, m), 3.34 (3H, s), 3.72-3.81 (1H, m), 3.84 (2H, s), 4.08-4.17 (1H, m), 4.21 (2H, t, J=6.0 Hz), 6.47 (1H, d, J=7.0 Hz), 6.67 (1H, d, J=2.0 Hz), 7.13-7.22 (4H, m), 7.74 (1H, d, J=2.0 Hz)

Example 731 1-Ethyl-7-{[(2-hydroxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

To a ethanol solution (20 ml) of tert-butyl (1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)methyl((2-(hydroxymethyl)pyridin-3-yl)methyl)carbamate (0.82 g) was added 5 M HCl and the mixture was stirred at 50° C. for 7 hours. The resulting mixture was concentrated and then 5 M NaOH was added thereto. Organic materials were extracted with ethyl acetate twice and then dried over MgSO₄. After evaporation, the residue was purified by column chromatography (methanol/ethyl acetate 1:9→1:1) to give the titled compound as pale yellow oil (0.37 g).

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.0 Hz), 1.53 (3H, s), 3.42 (3H, s), 3.74-3.90 (5H, m), 4.09-4.19 (1H, m), 4.80 (2H, s), 7.20-7.29 (4H, m), 7.64-7.67 (1H, m), 8.49-8.51 (1H, m).

Example 732 1-Ethyl-7-{[(5-methoxymethyl-2-methyl-2H-pyrazol-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3, t, J=7.0 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.42 (3H, s), 3.77-3.87 (5H, m), 4.11-1.18 (1H, m), 4.41 (2H, s), 6.18 (1H, s), 7.21-7.28 (3H, m).

Example 733 1-Isobutyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.75 (3H, s), 0.77 (3H, s), 0.98 (3H, br), 1.53 (3H, br), 1.76-1.84 (1H, m), 2.56 (3H, s), 3.37-3.42 (1H, m), 3.82 (2H, s), 3.85 (2H, s), 4.34-4.40 (1H, m), 7.00-7.02 (1H, m), 7.10-7.14 (1H, m), 7.20-7.23 (1H, m), 7.24-7.27 (1H, m), 7.62 (1H, br), 7.62-7.64 (1H, m), 8.41 (1H, dd, J=4.9, 1.7 Hz).

Example 734 1-Isobutyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.74 (3H, s), 0.76 (3H, s), 0.98 (3H, br), 1.53 (3H, br), 1.74-1.85 (1H, m), 3.39-3.42 (1H, m), 3.40 (3H, s), 3.82 (2H, s), 3.90 (2H, s), 4.34-4.39 (1H, m), 7.01-7.02 (1H, m), 7.18-7.21 (1H, m), 7.23-7.27 (2H, m), 7.68 (1H, br), 7.74 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 735 1-(2-Methoxyethyl)-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.01 (3H, br), 1.53 (3H, br), 2.56 (3H, s), 3.34 (3H, s), 3.49 (1H, br), 3.60 (1H, br), 3.81 (2H, s), 3.84 (2H, s), 3.98 (1H, br), 4.11 (1H, br), 7.00 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.22 (1H, dd, J=8.4, 1.8 Hz), 7.58 (1H, d, J=8.4 Hz), 7.64 (1H, dd, J=7.6, 1.5 Hz), 7.92 (1H, br), 8.41 (1H, dd, J=4.9, 1.5 Hz).

Example 736 1-(2-Methoxyethyl)-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.01 (3H, br), 1.53 (3H, br), 3.34 (3H, s), 3.41 (3H, s), 3.59 (1H, br), 3.72 (1H, br), 3.81 (2H, s), 3.89 (2H, s), 3.98 (1H, br), 4.10 (1H, br), 4.67 (2H, s), 6.98-7.00 (1H, m), 7.21 (1H, dd, J=8.4, 1.9 Hz), 7.24-7.27 (1H, m), 7.57 (1H, d, J=8.4 Hz), 7.66 (1H, br), 7.73 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 737 1-Cyclopropylmethyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.18 (2H, br), 0.41 (2H, d, J=8.0 Hz), 0.96-1.07 (4H, m), 1.54 (3H, br), 3.65 (1H, br), 3.82 (2H, s), 3.85 (2H, s), 4.11 (1H, br), 7.03 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.21 (1H, dd, J=8.4, 1.8 Hz), 7.32 (1H, d, J=8.4 Hz), 7.63 (1H, dd, J=7.6, 1.6 Hz), 7.84 (1H, br), 8.41 (1H, dd. J=4.9, 1.6 Hz).

Example 738 1-Cyclopropylmethyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.19 (2H, br), 0.40 (2H, d, J=8.1 Hz), 0.97-1.07 (4H, m), 1.54 (3H, br), 3.41 (3H, s), 3.66 (1H, br), 3.82 (2H, s), 3.90 (2H, s), 4.10 (1H, br), 4.67 (2H, s), 7.04 (1H, d, J=1.8 Hz), 7.20 (1H, dd, J=8.4, 1.8 Hz), 7.23-7.26 (1H, m), 7.32 (1H, d, J=8.4 Hz), 7.74 (1H, dd, J=7.7, 1.6 Hz), 8.07 (1H, br), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 739 1-Cyclopropyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.40 (2H, br), 1.00 (2H, br), 1.54 (6H, br), 2.56 (3H, s), 3.16-3.22 (1H, m), 3.82 (2H, s), 3.85 (2H, s), 6.99 (1H, br), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.23 (1H, dd, J=8.4, 1.9 Hz), 7.34 (1H, d, J=8.4 Hz), 7.64 (1H, dd, J=7.6, 1.6 Hz), 8.13 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).

Example 740 1-Cyclopropyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.40 (2H, br), 1.00 (2H, br), 1.54 (6H, br), 3.16-3.21 (1H, m), 3.41 (3H, s), 3.82 (2H, s), 3.90 (2H, s), 4.67 (2H, s), 6.96 (1H, br), 7.21 (1H, dd, J=8.4, 1.9 Hz), 7.24-7.26 (1H, m), 7.34 (1H, d, J=8.4 Hz), 7.60 (1H, br), 7.74 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 741 N-[3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethy[l]benzenesulfonamide

Tributyl phosphine (1.2 ml) and 1,1′-(azodicarbonyl)dipiperidine (1.17 g) were added to a toluene solution (100 ml) of 2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)-ethyl]-benzenesulfonamide (1.39 g), and 1-ethyl-7-(3-hydroxy-propyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.94 g). The mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and saturated saline, dried with magnecium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→1:0). The purified product was condensed under reduced pressure to produce the title compound (0.54 g) as a white amorphous.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.91-2.01 (2H, m), 2.61 (2H, t, J=7.7 Hz), 3.31-3.51 (2H, m), 3.40 (3H, s), 3.70 (2H, t, J=6.7 Hz), 3.72-3.81 (1H, m), 4.09-4.17 (1H, m), 4.22 (2H, t, J=6.7 Hz), 6.45 (1H, d, J=7.3 Hz), 6.94 (1H, dd, J=8.4 and 1.9 Hz), 7.02 (1H, d, J=1.9 Hz), 7.12-7.16 (2H, m), 7.46-7.66 (6H, m), 7.90-7.94 (1H, m), 8.34 (1H, d, J=7.5 Hz)

Example 742 1-Ethyl-3,3,5-trimethyl-7-{3-[2-(1-oxo-1H-isoquinolin-2-yl)ethylamino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Lithium hydroxide (3.2 g), and thioglycolic acid (2.4 ml) were added to a DMF solution (27.4 ml) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide (4.56 g). The mixture was stirred at room temperature for 1 hour. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed under reduced pressure to produce the title compound (2.24 g) as a yellow oil.

¹H NMR (CDCl₃), δppm: 0.80 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.77-1.88 (2H, m), 2.64-2.72 (4H, m), 3.04 (2H, t, J=6.3 Hz), 3.38 (3H, s), 3.69-3.80 (1H, m), 4.08-4.17 (3H, m), 6.51 (1H, d, J=7.3 Hz), 7.00-7.03 (2H, m), 7.11-7.17 (2H, m), 7.46-7.53 (2H, m), 7.61-7.66 (1H, m), 8.42 (1H, dd, J=8.0 and 0.6 Hz)

Example 743 1-Cyclopropyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.12-0.19 (1H, m), 0.60-0.67 (1H, m), 0.75-0.83 (1H, m), 0.85 (3H, s), 1.24-1.28 (1H, m), 1.52 (3H, s), 3.15-3.21 (1H, m), 3.39 (3H, s), 3.40 (3H, s), 3.84 (2H, s), 3.91 (2H, s), 4.67 (2H, s), 7.19-7.20 (1H, m), 7.22-7.29 (2H, m), 7.33 (1H, d, J=4.3 Hz), 7.73 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 744 1-Isobutyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.70 (3H, d, J=6.7 Hz), 0.75 (3H, d, J=6.7 Hz), 0.81 (3H, s), 1.53 (3H, s), 1.75-1.86 (1H, m), 3.31 (1H, dd, J=13.6, 6.4 Hz), 3.85 (2H, s), 3.91 (2H, s), 4.37 (1H, dd, J=13.6, 8.6 Hz), 4.67 (2H, s), 7.23-7.26 (4H, m), 7.72 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 745 1-(2-Methoxyethyl)-3,3,5-trimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.85 (3H, s), 1.53 (3H, s), 2.56 (3H, s), 3.29 (3H, s), 3.41 (3H, s), 3.53-3.58 (1H, m), 3.69 (1H, ddd, J=10.3, 7.1, 4.4 Hz), 3.82 (2H, s), 3.87 (2H, s), 3.97 (1H, ddd, J=14.1, 5.2, 4.6 Hz), 4.07-4.15 (1H, m), 7.13 (1H, dd, J=7.6, 4.9 Hz), 7.23-7.26 (2H, m), 7.50 (1H, d, J=8.2 Hz), 7.63 (1H, dd, J=7.6, 1.6 Hz), 8.42 (1H, dd, J=4.8, 1.6 Hz).

Example 746 1-Isobutyl-3,3-dimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.76 (6H, d, J=6.7 Hz), 0.98 (3H, s), 1.53 (3H, s), 1.78-1.89 (1H, m), 2.55 (3H, s), 3.41 (1H, dd, J=13.8, 6.5 Hz), 3.80 (2H, s), 3.87 (2H, s), 4.37 (1H, dd, J=13.8, 8.3 Hz), 6.97 (1H, d, J=8.1 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.19 (1H, dd, J=8.1, 1.7 Hz), 7.32 (1H, d, J=1.7 Hz), 7.62 (1H, dd, J=7.6, 1.6 Hz), 7.70 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).

Example 747 1-Isobutyl-8-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.76 (6H, d, J=6.7 Hz), 0.98 (3H, s), 1.53 (3H, s), 1.78-1.89 (1H, m), 3.39-3.46 (1H, m), 3.40 (3H, s), 3.83 (2H, s), 3.88 (2H, s), 4.33-4.42 (1H, m), 4.66 (2H, s), 6.97 (1H, d, J=8.1 Hz), 7.18 (1H, dd, J=8.1, 1.7 Hz), 7.23-7.26 (1H, m), 7.31 (1H, d, J=1.7 Hz), 7.72 (1H, dd, J=7.6, 1.6 Hz), 7.73 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).

Example 748 1-Cyclopropylmethyl-3,3-dimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.18 (2H, br), 0.41 (2H, d, J=7.9 Hz), 0.95-1.08 (4H, m), 1.54 (3H, br), 2.55 (3H, s), 3.70 (1H, br), 3.80 (2H, s), 3.87 (2H, s), 4.14 (1H, br), 6.97 (1H, d, J=8.1 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.19 (1H, dd, J=8.1, 1.6 Hz), 7.39 (1H, d, J=1.6 Hz), 7.62 (1H, dd, J=7.6, 1.6 Hz), 7.74 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).

Example 749 1-Cyclopropylmethyl-8-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.18 (2H, br), 0.41 (2H, d, J=7.9 Hz), 0.95-1.08 (4H, m), 1.54 (3H, br), 3.40 (3H, s), 3.71 (1H, br), 3.84 (2H, s), 3.89 (2H, s), 4.10 (1H, br), 4.66 (2H, s), 6.97 (1H, d, J=8.1 Hz), 7.18 (1H, dd, J=8.1, 1.6 Hz), 7.23-7.26 (1H, m), 7.37 (1H, d, J=1.6 Hz), 7.72 (1H, dd, J=7.7, 1.6 Hz), 7.83 (1H, br), 8.41 (1H, dd, J=4.8, 1.6 Hz).

Example 750 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methoxymethylpyridin-3-ylmethyl)carbamic acid tert-butyl ester

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-1-oxypyridin-3-ylmethyl) carbamic acid tert-butyl ester (188 mg) was dissolved in DMF (20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 19.7 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.028 ml) was added thereto, and the mixture was stirred at 0° C. for 0.5 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (162 mg) as a colorless oil.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.48 (9H, bs), 1.53 (3H, s), 3.33 (3H, s), 3.36 (3H, s), 3.74-3.84 (1H, m), 4.08-4.18 (1H, m), 4.30-4.50 (2H, m), 4.52-4.72 (4H, m), 7.02-7.15 (2H, m), 7.20-7.25 (2H, m), 7.46-7.57 (1H, m), 8.46 (1H, dd, J=1.5 and 4.8 Hz)

Example 751

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl)carbamic acid tert-butyl ester

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-1-oxypyridin-3-ylmethyl)carbamic acid tert-butyl ester (2.35 g) was dissolved in acetic anhydride (20 ml). The reaction mixture was stirred at 100° C. for 2 h. The resulting mixture was evaporated, and dissolved in MeOH (15 ml). Potassium carbonate (6.8 g) was added to the mixture, and the reaction mixture was stirred 2 h at room temperature. Water was added to the resulting mixture and then the mixture was extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (536 mg) as a pale yellow amorphous.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.49 (9H, s), 1.52 (3H, s), 2.37 (3H, s), 3.37 (3H, s), 3.77-3.83 (1H, m), 4.09-4.15 (1H, m), 4.30-4.52 (4H, m), 7.00-7.08 (2H, m), 7.09-7.15 (1H, m), 7.25-7.30 (1H, m), 8.07 (1H, d, J=2.6 Hz)

Example 752 1-Ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-yl-ethylamino)propyl]-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 742 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.53 (3H, s), 1.78-1.85 (2H, m), 2.63-2.72 (4H, m), 2.79-2.83 (2H, m), 2.86-2.92 (2H, m), 3.40 (3H, s), 3.73-3.81 (1H, m), 4.09-4.18 (1H, m), 7.01-7.06 (2H, m), 7.19-7.23 (2H, m), 7.52-7.55 (1H, m), 8.47-8.49 (2H, m)

Example 753 1-Ethyl-3,3,5-trimethyl-7-{3-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethylamino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 742 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.84 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.73-1.84 (2H, m), 2.60-2.71 (4H, m), 3.03 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.73-3.81 (1H, m), 4.09-4.18 (1H, m), 4.17 (2H, t, J=6.2 Hz), 6.47 (1H, d, J=7.0 Hz), 6.66 (1H, d, J=2.0 Hz), 6.98-7.05 (2H, m), 7.14-7.20 (2H, m), 7.74 (1H, d, J=2.0 Hz)

Example 754 Acetic acid 3-{[N-tert-butoxycarbonyl-N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)amino]methyl}pyridin-2-ylmethyl ester

The synthesis of the title compound was performed in the same manner as in Example 751 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.19 (3H, t, J=7.1 Hz), 1.48 (9H, br), 1.57 (3H, s), 2.08 (3H, s), 3.36 (3H, s), 3.75-3.84 (1H, m), 4.09-4.18 (1H, m), 4.41 (2H, br), 4.57 (2H, br), 5.15 (2H, s), 7.03-7.12 (2H, m), 7.22-7.26 (2H, m), 7.47-7.50 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz).

Example 755 Acetic Acid 3-{[(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)amino]methyl}pyridin-2-ylmethyl ester

The synthesis of the title compound was performed in the same manner as in Example 731 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.11 (3H, s), 3.41 (3H, s), 3.74-3.82 (1H, m), 3.86 (2H, s), 3.90 (2H, s), 4.09-4.20 (1H, m), 5.33 (2H, s), 7.23-7.27 (4H, m), 7.72 (1H, d, J=7.7 Hz), 8.52-8.54 (1H, m).

Example 756 1-Ethyl-3,3,5-trimethyl-7-{3-[2-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethylamino]propyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 742 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.81 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 1.76-1.83 (2H, m), 2.63-2.70 (4H, m), 3.01 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.72-3.81 (1H, m), 4.09-4.18 (3H, m), 6.54 (1H, dd, J=7.4 and 0.8 Hz), 6.96-7.04 (3H, m), 7.19 (1H, d, J=8.6 Hz), 7.23 (1H, d, J=7.4 Hz), 7.49 (1H, d, J=2.1 Hz),

Example 757 N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(6-methoxy-2-methylpyridin-3-ylmethyl)carbamic acid tert-butyl ester

N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl)carbamic acid tert-butyl ester (536 mg) was dissolved in DMF (20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 56.1 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.081 ml) was added thereto, and the mixture was stirred at 0° C. for 0.5 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (550 mg) as a yellow oil.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.50 (9H, s), 1.53 (3H, s), 2.37 (3H, s), 3.36 (3H, s), 3.75-3.85 (4H, m), 4.09-4.20 (1H, m), 4.30-4.50 (4H, m), 6.85-6.98 (1H, m), 7.00-7.12 (2H, m), 7.23-7.28 (1H, m), 8.08 (1H, d, J=2.8 Hz)

Example 758 1-Ethyl-7-{[(6-methoxy-2-methyl-pyridin-3-ylmethyl)amino]methyl}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 670 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.83 (3H, s), 1.18 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.47 (3H, s), 3.42 (3H, s), 3.78-3.83 (3H, m), 3.85 (3H, s), 3.88 (2H, s), 4.10-4.17 (1H, m), 7.20-7.30 (4H, m), 8.10 (1H, d, J=2.9 Hz)

Example 759 1,3,3-Trimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.08 (3H, br), 1.63 (3H, br), 2.56 (3H, s), 3.47 (3H, s), 3.81 (2H, s), 3.87 (2H, s), 6.97 (1H, d, J=8.1 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.19 (1H, dd, J=8.1, 1.7 Hz), 7.24-7.26 (1H, m), 7.62 (1H, dd, J=7.6, 1.6 Hz), 7.98 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).

Example 760 1-Ethyl-3,3-dimethyl-8-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.00 (3H, br), 1.26 (3H, t, J=7.1 Hz), 1.55 (3H, br), 2.56 (3H, s), 3.81 (2H, s), 3.87 (2H, s), 3.93 (1H, br), 4.09 (1H, br), 6.93-6.97 (1H, m), 7.12 (1H, dd, J=7.5, 4.9 Hz), 7.19 (1H, dd, J=8.2, 1.8 Hz), 7.24-7.26 (1H, m), 7.35 (1H, br), 7.63 (1H, dd, J=3.5, 1.5 Hz), 8.41 (1H, dd, J=4.8, 1.5 Hz).

Example 761 1,3,3-Trimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.05 (3H, br), 1.55 (3H, br), 2.56 (3H, s), 3.46 (3H, s), 3.82 (2H, s), 3.85 (2H, s), 7.03 (1H, br), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.20-7.23 (2H, m), 7.63 (1H, dd, J=7.6, 1.6 Hz), 8.03 (1H, br), 8.41 (1H, dd, J=4.9, 1.6 Hz).

Example 762 1-Ethyl-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.00 (3H, br), 1.22 (3H, t, J=7.1 Hz), 1.53 (3H, br), 2.56 (3H, s), 3.82 (2H, s), 3.85 (2H, s), 3.92 (1H, br), 4.12 (1H, br), 7.02 (1H, d, J=1.6 Hz), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.22 (1H, dd, J=8.4, 1.8 Hz), 7.29, (1H, d, J=8.4 Hz), 7.63 (1H, dd, J=7.6, 1.5 Hz), 7.85 (1H, br), 8.41 (1H, dd, J=4.9, 1.5 Hz).

Example 763 1-Ethyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.00 (3H, br), 1.22 (3H, t, J=7.1 Hz), 1.53 (3H, br), 3.41 (3H, s), 3.82 (2H, s), 3.90 (2H, s), 3.92 (1H, br), 4.08 (1H, br), 4.67 (2H, s), 7.01 (1H, d, J=1.5 Hz), 7.21 (1H, dd, J=8.4, 1.9 Hz), 7.23-7.29 (2H, m), 7.74 (1H, dd, J=7.7, 1.6 Hz), 7.79 (1H, br), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 764 8-{[(2-Methoxymethyl-pyridin-3-ylmethyl)amino]methyl}-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.02 (3H, br), 1.53 (3H, br), 3.40 (3H, s), 3.47 (3H, s), 3.84 (2H, s), 3.90 (2H, s), 4.67 (2H, s), 6.97 (1H, d, J=8.2 Hz), 7.18 (1H, dd, J=8.2, 1.7 Hz), 7.23-7.26 (2H, m), 7.72 (1H, dd, J=7.7, 1.6 Hz), 7.94 (1H, br), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 765 5-Cyclopropylmethyl-1-(2-methoxyethyl)-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.12-0.22 (2H, m), 0.34-0.50 (2H, m), 0.82 (3H, s), 0.94-1.03 (1H, m), 1.53 (3H, s), 2.56 (3H, s), 3.31 (3H, s), 3.49-3.60 (2H, m), 3.70 (1H, ddd, J=10.0, 7.1, 5.5 Hz), 3.81 (2H, s), 3.87 (2H, s), 3.94 (1H, dt, J=13.9, 5.3 Hz), 4.12 (1H, dd, J=14.1, 7.4 Hz), 4.15-4.22 (1H, m), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.24-7.26 (2H, m), 7.33 (1H, br), 7.50 (1H, d, J=8.4 Hz), 7.63 (1H, dd, J=7.6, 1.6 Hz), 8.41 (1H, dd, J=4.9, 1.6 Hz).

Example 766 5-Cyclopropylmethyl-1-(2-methoxyethyl)-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]-methyl}-3,3-dimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.12-0.23 (2H, m), 0.34-0.44 (2H, m), 0.82 (3H, s), 0.96-1.03 (1H, m), 1.53 (3H, s), 3.30 (3H, s), 3.40 (3H, s), 3.49-3.60 (2H, m), 3.69 (1H, ddd, J=10.0, 7.1, 5.5 Hz), 3.84 (2H, s), 3.89 (2H, s), 3.95 (1H, dt, J=13.9, 5.3 Hz), 4.11-4.22 (2H, m), 4.66 (2H, s), 7.23-7.26 (2H, m), 7.32 (1H, br), 7.49 (1H, d, J=8.4 Hz), 7.72 (1H, dd, J=7.6, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 767 1-Cyclopropylmethyl-5-(2-methoxyethyl)-3,3-dimethyl-7-{[(2-methylpyridin-3-ylmethyl)-amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.11-0.22 (2H, m), 0.34-0.44 (2H, m), 0.82 (3H, s), 0.94-1.03 (1H, m), 1.52 (3H, s), 2.56 (3H, s), 3.29 (3H, s), 3.49-3.57 (2H, m), 3.71 (1H, ddd, J=10.0, 7.1, 5.5 Hz), 3.82 (2H, s), 3.87 (2H, s), 3.97 (1H, dt, J=13.9, 5.2 Hz), 4.11-4.22 (2H, m), 7.12 (1H, dd, J=7.6, 4.9 Hz), 7.23-7.27 (2H, m), 7.55 (1H, d, J=1.3 Hz), 7.64 (1H, dd, J=7.6, 1.6 Hz), 8.40 (1H, dd, J=4.9, 1.6 Hz).

Example 768 1-Cyclopropylmethyl-5-(2-methoxyethyl)-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]-methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.11-0.22 (2H, m), 0.34-0.44 (2H, m), 0.82 (3H, s), 0.94-1.04 (1H, m), 1.52 (3H, s), 3.29 (3H, s), 3.40 (3H, s), 3.48-3.57 (2H, m), 3.70 (1H, ddd, J=10.0, 7.0, 5.6 Hz), 3.85 (2H, s), 3.90 (2H, s), 3.96 (1H, dt, J=13.9, 5.3 Hz), 4.14 (1H, dd, J=14.1, 7.4 Hz), 4.18-4.25 (1H, m), 4.67 (2H, s), 7.23-7.29 (3H, m), 7.52 (1H, br), 7.75 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 769 5-Cyclopropyl-1-cyclopropylmethyl-7-{[(2-methoxymethylpyridin-3-ylmethyl)amino]methyl}-3,3-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 721 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.00-0.06 (1H, m), 0.07-0.13 (1H, m), 0.18-0.35 (3H, m), 0.58-0.65 (1H, m), 0.75-0.90 (2H, m), 0.84 (3H, s), 1.14-1.22 (1H, m), 1.51 (3H, s), 3.20-3.25 (1H, m), 3.36 (1H, dd, J=14.1, 6.8 Hz), 3.40 (3H, s), 3.86 (2H, s), 3.90 (2H, s), 4.30 (1H, dd, J=14.1, 7.4 Hz), 4.67 (2H, s), 7.18-7.26 (3H, m), 7.36 (1H, br), 7.73 (1H, dd, J=7.7, 1.6 Hz), 8.50 (1H, dd, J=4.8, 1.6 Hz).

Example 770 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 165.3-166.5° C.

Example 771 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylpyridin-3-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 155.1-155.8° C.

Example 772 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-2-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.78 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.23 (3H, d, J=0.9 Hz), 2.42 (3H, d, J=0.8 Hz), 2.76 (2H, t, J=7.4 Hz), 2.84-2.92 (2H, m), 2.95-3.04 (2H, m), 3.36 (3H, s), 3.71-3.79 (1H, m), 4.01 and 4.02 (2H, s), 4.03-4.16 (3H, m), 6.77 (1H, br), 6.93 (1H, br), 6.97-7.01 (m, 3H), 7.12 (1H, d, J=9.0 Hz), 7.52 (1H, d, J=2.1 Hz).

Example 773 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-2-ylmethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.41 (3H, s), 2.42 (3H, s), 2.75 (2H, t, J=7.4 Hz), 2.83-2.91 (2H, m), 2.99 (2H, t, J=6.4 Hz), 3.36 (3H, s), 3.72-3.79 (1H, m), 4.01 (2H, s), 4.07 (2H, t, J=6.4 Hz), 4.09-4.16 (1H, m), 6.43 (1H, d, J=7.3 Hz), 6.55 (1H, s), 6.77 (1H, br), 6.98-7.02 (m, 2H), 7.06 (1H, d, J=7.3 Hz), 7.13 (1H, d, J=8.7 Hz).

Example 774 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-2-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.24 (3H, s), 2.41 (3H, d, J=0.9 Hz), 2.79-2.85 (2H, m), 2.88-2.93 (2H, m), 2.95 (2H, t, J=6.8 Hz), 3.37 (3H, s), 3.71-3.79 (1H, m), 3.89 (2H, s), 3.94-3.98 (2H, m), 4.10-4.17 (1H, m), 6.34 (1H, d, J=7.4 Hz), 6.53 (1H, br), 6.89 (1H, d, J=7.4 Hz), 7.01 (1H, d, J=1.8 Hz), 7.04 (1H, dd, J=1.8, 8.3 Hz), 7.12 (1H, dd, J=4.8, 7.6 Hz), 7.16 (1H, d, J=8.30 Hz), 7.37 (1H, dd, J=1.1, 7.6 Hz), 8.39 (1H, dd, J=1.1, 4.8 Hz).

Example 775 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-2-ylmethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.80 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.17 (3H, d, J=1.0 Hz), 2.22 (3H, s), 2.81-2.87 (2H, m), 2.89-2.97 (4H, m), 3.38 (3H, s), 3.71-3.80 (1H, m), 3.88 (2H, s), 3.93-4.00 (2H, m), 4.09-4.18 (1H, m), 6.70 (1H, br), 6.96 (1H, d, J=2.1 Hz), 7.03 (1H, d, J=1.8 Hz), 7.06 (1H, dd, J=1.8, 8.3 Hz), 7.11 (1H, dd, J=4.8, 7.6 Hz), 7.17 (1H, d, J=8.3 Hz), 7.34 (1H, dd, J=1.2, 7.6 Hz), 7.50 (1H, d, J=2.1 Hz), 8.39 (1H, dd, J=1.2, 4.8 Hz).

Example 776 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(3-methylpyridin-2-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.14 (3H, d, J=1.0 Hz), 2.23 (3H, s), 2.42 (3H, d, J=1.0 Hz), 2.80-2.86 (2H, m), 2.88-2.96 (4H, m), 3.38 (3H, s), 3.71-3.79 (1H, m), 3.88 (2H, s), 3.91-3.99 (2H, m), 4.10-4.16 (1H, m), 6.54 (1H, br), 6.63 (1H, br), 7.02 (1H, d, J=1.9 Hz), 7.05 (1H, dd, J=1.9, 8.3 Hz), 7.12 (1H, dd, J=4.8, 7.6 Hz), 7.16 (1H, d, J=8.3 Hz), 7.36 (1H, dd, J=1.1, 7.6 Hz), 8.39 (1H, dd, J=1.1, 4.8 Hz).

Example 777 N-[2-({N′-[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl]-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.42 (3H, d, J=1.0 Hz), 2.78-2.98 (6H, m), 3.03 (3H, s), 3.36 (3H, s), 3.70-3.83 (1H, m), 3.88 (2H, s), 4.06-4.22 (3H, m), 6.43-6.45 (1H, m), 6.53 (1H, t, J=0.92 Hz), 6.97 (1H, d, J=1.8 Hz), 6.99-7.03 (1H, m), 7.04 (1H, d, J=7.4 Hz), 7.06-7.11 (1H, m), 7.14-7.18 (1H, m), 7.19 (1H, d, J=8.4 Hz), 7.30-7.35 (1H, m), 7.44 (1H, dd, J=0.96, 8.1 Hz), 9.88 (1H, bs).

Example 778 N-[2-({N′-[2-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl]-N′-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)phenyl]methanesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.0 Hz), 1.52 (3H, s), 2.24 (3H, s), 2.79-2.97 (6H, m), 3.01 (3H, s), 3.36 (3H, s), 3.71-3.83 (1H, m), 3.87 (2H, s), 4.06-4.20 (3H, m), 6.87 (1H, d, J=1.0 Hz), 6.94-6.99 (2H, m), 7.02 (1H, dd, J=1.9, 8.3 Hz), 7.05-7.13 (1H, m), 7.13-7.18 (1H, m), 7.19 (1H, d, J=8.3 Hz), 7.29-7.36 (1H, m), 7.43 (1H, d, J=8.0 Hz), 7.53 (1H, d, J=2.1 Hz), 9.84 (1H, bs).

Example 779 N-[2-({N′-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N′-[2-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)ethyl]amino}methyl)phenyl]methanesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.17 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.21 (3H, d, J=1.0 Hz), 2.43 (3H, d, J=1.0 Hz), 2.78-2.97 (6H, m), 3.02 (3H, s), 3.36 (3H, s), 3.72-3.85 (1H, m), 3.87 (2H, s), 4.04-4.19 (3H, m), 6.54 (1H, d, J=1.2 Hz), 6.81 (1H, d, J=1.1 Hz), 6.97 (1H, d, J=1.9 Hz), 7.01 (1H, dd, J=1.9, 8.3 Hz), 7.06-7.13 (1H, m), 7.13-7.17 (1H, m), 7.19 (1H, d, J=8.3 Hz), 7.29-7.36 (1H, m,), 7.44 (1H, dd, J=0.92, 8.1 Hz), 9.75 (1H, bs).

Example 780 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 168.5-170.5° C.

Example 781 7-(2-{N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 133.5-139.7° C.

Example 782 7-(2-{N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}ethyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

White powder

mp: 171-172.9° C.

Example 783 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.39 (3H, s), 2.42 (3H, s), 2.70-2.85 (4H, m), 2.91 (2H, t, J=6.4 Hz), 3.36 (3H, s), 3.71-3.78 (1H, m), 3.83 (2H, s), 4.03 (2H, t, J=6.4 Hz), 4.06-4.16 (1H, m), 6.42 (1H, dd, J=0.8 and 7.4 Hz), 6.55 (1H, t, J=1.0 Hz), 6.95-7.02 (3H, m), 7.13 (1H, d, J=8.8 Hz), 8.58 (1H, s)

Example 784 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 2.70-2.85 (4H, m), 2.88-2.95 (2H, m), 3.36 (3H, s), 3.70-3.80 (1H, m), 3.82 (2H, s), 4.00-4.18 (3H, m), 6.86 (1H, d, J=1.0 Hz), 6.95-7.03 (3H, m), 7.12 (1H, d, J=8.2 Hz), 7.52 (1H, d, 2.1 Hz), 8.59 (1H, s)

Example 785 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(4-methylthiazol-5-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.79 (3H, s), 1.16 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.21 (3H, s), 2.39 (3H, s), 2.43 (3H, s), 2.70-2.85 (4H, m), 2.88-2.96 (2H, m), 3.36 (3H, s), 3.70-3.85 (3H, m), 3.96-4.18 (3H, m), 6.56 (1H, d, J=1.1 Hz), 6.79 (1H, d, J=1.1 Hz), 6.95-7.00 (2H, m), 7.12 (1H, d, J=8.6 Hz), 8.60 (1H, s)

The following compounds shown in Examples 786 to 791, Examples 793 and Example 795 to 802 can be prepared by the same manner as mentioned above or a conventional manner using appropriate starting materials.

Example 786 1-Ethyl-3,3,5-trimethyl-7-{2-[N-(2-methylpyridin-3-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 787 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(7-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]ethyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 788 7-{2-[N-[2-(2,7-Dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyridin-3-ylmethyl)amino]ethyl}-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 789 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-methylpyrimidin-5-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 790 N-[3-({N′-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]amino}methyl)pyridin-2-yl]methanesulfonamide Example 791 N-[3-({N′-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N′-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-yl]acetamide Example 792 Acetic acid 3-({N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridin-2-ylmethyl ester dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

¹H NMR (DMSO-dd, δppm: 0.69 (3H, s), 1.04 (3H, t, J=6.9 Hz), 1.34 (3H, s), 2.01-2.04 (3H, m), 2.42 (3H, s), 2.74 (2H, br), 3.26 (3H, s), 3.45-4.30 (8H, m), 5.10 (2H, br), 6.48 (1H, br), 6.64 (1H, br), 7.17 (1H, br), 7.31 (2H, br), 7.48 (2H, br), 7.79 (1H, br), 8.46 (1H, br).

Example 793 1-Ethyl-7-({N-(2-imidazol-1-ylmethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 794 1-Ethyl-7-({N-(3-imidazol-1-ylmethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.77 (3H, s), 1.17 (3H, t, J=7.0 Hz), 1.51 (3H, s), 2.43 (3H, d, J=1.0 Hz), 2.79 (2H, dt, J=2.1, 5.9 Hz), 3.32 (3H, s), 3.55-3.68 (4H, m), 3.71-3.83 (1H, m), 3.99-4.17 (3H, m), 5.02 (2H, s), 6.43 (1H, dd, J=0.74, 7.3 Hz), 6.49 (1H, t, J=1.0 Hz), 6.88 (1H, t, J=1.3 Hz), 6.95 (1H, d, J=7.3 Hz), 6.98-7.07 (3H, m), 7.07-7.15 (3H, m), 7.15-7.25 (2H, m), 7.52 (1H, d, J=1.1 Hz).

Example 795 1-Ethyl-7-({N-(2-imidazol-1-ylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 796 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-morpholin-4-ylbenzyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 797 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-[1,2,4]triazol-1-yl-benzyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 798 1-Ethyl-7-(N-{imidazo[1,2-a]pyridin-8-ylmethyl-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 799 1-Ethyl-7-(N-{imidazo[1,2-a]pyridin-6-ylmethyl-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 800 1-Ethyl-3,3,5-trimethyl-7-{[N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]-N-(2-pyrazol-1-ylpyridin-3-ylmethyl)amino]methyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 801 7-({N-(3H-Benzoimidazol-4-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione Example 802 1-Ethyl-7-({N-(4-methoxymethylpyridin-3-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione Example 802-a 1-Ethyl-3,3,5-trimethyl-7-{2-[N-[2-(2,7-dimethyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)-ethyl]-N-(4-methyl-thiazol-2-ylmethyl)-amino]-ethyl}-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 30 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.78 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.51 (3H, s), 2.20 (3H, d, J=0.9 Hz), 2.42 (3H, d, J=0.9 Hz), 2.43 (3H, d, J=0.9 Hz), 2.76 (2H, t, J=7.4 Hz), 2.85-2.90 (2H, m), 2.95-3.02 (2H, m), 3.35 (3H, s), 3.71-3.77 (1H, m), 4.01 and 4.02 (2H, s), 4.02-4.16 (3H, m), 6.57 (1H, br), 6.77 (1H, br), 6.86 (1H, br), 6.97-7.01 (m, 2H), 7.12 (1H, d, J=8.9 Hz).

Examples 803 to 1038

The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.

Example No. R1 MS(M + 1) 803

489 804

500 805

500 806

503 807

505 808

519 809

506 810

517 811

515 812

489 813

568 814

517 815

520 816

557 817

534 818

520 819

533 820

520 821

514 822

514 823

514 824

514 825

514 826

503 827

517 828

503 829

514 830

518 831

568 832

530 833

506 834

506 835

501 836

490 837

501 838

514 839

530 840

504 841

514 842

490 843

490 844

504 845

588 846

515 847

528

Example No. R1 MS(M + 1) 848

545 849

556 850

556 851

559 852

561 853

575 854

562 855

573 856

571 857

545 858

624 859

573 860

576 861

613 862

590 863

576 864

589 865

576 866

570 867

570 868

570 869

570 870

570 871

574 872

559 873

590 874

573 875

559 876

570 877

574 878

624 879

586 880

562 881

562 882

557 883

546 884

557 885

570 886

586 887

560 888

570 889

546 890

546 891

560 892

644 893

571 894

584

Example No. R1 MS(M + 1) 895

555 896

566 897

566 898

569 899

571 900

585 901

572 902

583 903

581 904

555 905

634 906

583 907

586 908

623 909

600 910

586 911

599 912

586 913

580 914

580 915

580 916

580 917

580 918

584 919

569 920

600 921

583 922

569 923

580 924

584 925

634 926

596 927

572 928

572 929

567 930

556 931

567 932

580 933

596 934

570 935

580 936

556 937

556 938

570 939

654 940

581 941

594

Example No. R1 MS(M + 1) 942

545 943

556 944

556 945

559 946

561 947

575 948

562 949

573 950

571 951

545 952

624 953

573 954

576 955

613 956

590 957

576 958

589 959

576 960

570 961

570 962

570 963

570 964

570 965

574 966

559 967

590 968

573 969

559 970

570 971

574 972

624 973

586 974

562 975

562 976

557 977

546 978

557 979

570 980

586 981

560 982

570 983

546 984

546 985

560 986

644 987

571 988

584

Example No. R1 MS(M + 1) 989

406 990

421 991

448 992

434 993

452 994

436 995

440 996

392 997

448 998

438 999

435 1000

435 1001

421 1002

421 1003

438 1004

435 1005

406 1006

407 1007

420 1008

421 1009

419 1010

420 1011

450 1012

454 1013

426 1014

452 1015

407 1016

452 1017

422 1018

450 1019

436 1020

422 1021

436 1022

452 1023

422 1024

422 1025

408 1026

435 1027

411 1028

422 1029

422 1030

434 1031

421 1032

496 1033

434 1034

448 1035

468 1036

449 1037

435 1038

435

Examples 1039 to 1614

The following compounds can be obtained in the same manner as in Examples above using appropriate starting materials.

Example No. R1 MS (M + 1) 1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

1071

1072

1073

1074

1075

1076

1077

1078

1079

1080

1081

1082

1083

1084

1085

1086

Example No. R1 MS (M + 1) 1087

1088

1089

1090

1091

1092

1093

1094

1095

1096

1097

1098

1099

1100

1101

1102

1103

1104

1105

1106

1107

1108

1109

1110

1111

1112

1113

1114

1115

1116

1117

1118

1119

1120

1121

1122

1123

1124

1125

1126

1127

1128

1129

1130

1131

1132

1133

1134

Example No. R1 MS (M + 1) 1135

1136

1137

1138

1139

1140

1141

1142

1143

1144

1145

1146

1147

1148

1149

1150

1151

1152

1153

1154

1155

1156

1157

1158

1159

1160

1161

1162

1163

1164

1165

1166

1167

1168

1169

1170

1171

1172

1173

1174

1175

1176

1177

1178

1179

1180

1181

1182

Example No. R1 MS (M + 1) 1183

1184

1185

1186

1187

1188

1189

1190

1191

1192

1193

1194

1195

1196

1197

1198

1199

1200

1201

1202

1203

1204

1205

1206

1207

1208

1209

1210

1211

1212

1213

1214

1215

1216

1217

1218

1219

1220

1221

1222

1223

1224

1225

1226

1227

1228

1229

1230

Example No. R1 MS (M + 1) 1231

1232

1233

1234

1235

1236

1237

1238

1239

1240

1241

1242

1243

1244

1245

1246

1247

1248

1249

1250

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1255

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1260

1261

1262

1263

1264

1265

1266

1267

1268

1269

1270

1271

1272

1273

1274

1275

1276

1277

1278

Example No. R1 MS (M + 1) 1279

1280

1281

1282

1283

1284

1285

1286

1287

1288

1289

1290

1291

1292

1293

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1300

1301

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1312

1313

1314

1315

1316

1317

1318

1319

1320

1321

1322

1323

1324

1325

1326

Example No. R1 MS (M + 1) 1327

1328

1329

1330

1331

1332

1333

1334

1335

1336

1337

1338

1339

1340

1341

1342

1343

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1345

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1347

1348

1349

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1356

1357

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1359

1360

1361

1362

1363

1364

1365

1366

1367

1368

1369

1370

1371

1372

1373

1374

Example No. R1 MS (M + 1) 1375

1376

1377

1378

1379

1380

1381

1382

1383

1384

1385

1386

1387

1388

1389

1390

1391

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1400

1401

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1408

1409

1410

1411

1412

1413

1414

1415

1416

1417

1418

1419

1420

1421

1422

Example No. R1 MS (M + 1) 1423

1424

1425

1426

1427

1428

1429

1430

1431

1432

1433

1434

1435

1436

1437

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1456

1457

1458

1459

1460

1461

1462

1463

1464

1465

1466

1467

1468

1469

1470

Example No. R1 MS (M + 1) 1471

1472

1473

1474

1475

1476

1477

1478

1479

1480

1481

1482

1483

1484

1485

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1505

1506

1507

1508

1509

1510

1511

1512

1513

1514

1515

1516

1517

1518

Example No. R1 MS (M + 1) 1519

1520

1521

1522

1523

1524

1525

1526

1527

1528

1529

1530

1531

1532

1533

1534

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1553

1554

1555

1556

1557

1558

1559

1560

1561

1562

1563

1564

1565

1566

Example No. R1 MS (M + 1) 1567

1568

1569

1570

1571

1572

1573

1574

1575

1576

1577

1578

1579

1580

1581

1582

1583

1584

1585

1586

1587

1588

1589

1590

1591

1592

1593

1594

1595

1596

1597

1598

1599

1600

1601

1602

1603

1604

1065

1606

1607

1608

1609

1610

1611

1612

1613

1614

Examples 1615 to 1625

The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.

Example No. R1 MS (M + 1) 1615

450 1616

450 1617

465 1618

438 1619

432 1620

445 1621

432 1622

460 1623

463 1624

459 1625

432

Pharmacological Test 1 (1) Production of Human Kv1.5-Expressing CHO-K1 Cell Lines

CHO-K1 cell lines stably expressing human Kv1.5 channels were prepared in the following manner.

Full-length human Kv1.5 cDNA was cloned from a human heart cDNA library (produced by Stratagene). The obtained human Kv1.5 sequence corresponds to the sequence described in FASEB J. 5, 331-337 (1991).

The obtained human Kv1.5 cDNA was inserted into a plasmid encoding a CMV promoter and a G418 resistance marker to produce a Kv1.5 expression vector. The human Kv1.5 expression vector was transfected into CHO-K1 cells by the lipofectamine method. After culturing the cells in an F-12 medium (produced by Invitrogen Corp.) containing 10% FBS (produced by Invitrogen Corp.) for 3 or 4 days, the medium was replaced with a FBS-containing F-12 medium that included 1,000 μg/ml of G418 (produced by Invitrogen Corp.), and single colonies were isolated. The amount of Kv1.5 channel expression in the single colonies was quantified at the mRNA level by RT-PCR and then quantified at the protein level by western blotting. Finally, the expressed current was analyzed by patch clamp method. Cell lines expressing a current of 200 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamp method.

(2) Production of CHO Cell Line Expressing Human GIRK1/4

CHO cell lines stably expressing human GIRK1/4 channels were prepared in the following manner.

Full-length human GIRK1 cDNA was cloned from HuH cell- and HeLa cell-derived cDNA libraries. Full-length GIRK4 cDNA was amplified from a human heart cDNA library (produced by Clontech Laboratories, Inc.) by PCR using synthetic primers shown in Table 1, and cloned into the Eco-RI restriction enzyme site of pCR-Blunt (produced by Invitrogen Corporation) or into the HincII site of pUC118 (produced by Takara Bio, Inc.).

TABLE 1 Primer Sequence hGIRK1-S 5′-ATGTCTGCACTCCGAAG SEQ ID GAAATTTG-3′ No. 1 hGIRK1-A 5′-TTATGTGAAGCGATCAG SEQ ID AGTTC-3′ No. 2 hGIRK1-F2 5′-GCAGGGTACCCCTTCGT SEQ ID ATTATGTCTGCACTCC-3′ No. 3 hGIRK1-A3 5′-GGTGTCTGCCGAGATTT SEQ ID GA-3′ No. 4 hGIRK1-A4  5′-CCGAGTGTAGGCGATCA SEQ ID CCC-3′ No. 5 hGIRK4-S 5′-ATGGCTGGCGATTCTAG SEQ ID GAATGCC-3′ No. 6 hGIRK4-A 5′-TCTCACCGAGCCCCTGG SEQ ID CCTCCC-3′ No. 7 hGIRK4-S2  5′-AACCAGGACATGGAGAT SEQ ID TGG-3′ No. 8 hGIRK4-A2 5′-GAGAACAGGAAAGCGGA SEQ ID CAC-3′ No. 9

The obtained human GIRK1 and GIRK4 cDNA sequences correspond to known sequences (NCBI database: GIRK1 (NM_(—)002239) and GIRK4 (NM_(—)000890) respectively). The obtained GIRK1 and GIRK4 cDNA sequences were cloned into the Eco-RI restriction enzyme site of pCR-Blunt (available from Invitrogen Corporation) or into the HincII site of pUC118 (available from Takara Bio, Inc.). A GIRK4 expression vector was constructed by insertion into the BamHI-XhoI site of pcDNA5/FRT. A GIRK1 expression vector was constructed by insertion into the KpnI-XhoI site of pcDNA3.1 (+) or pCAG_neo. FLP-IN-CHO cells (produced by Invitrogen Corporation) were transfected with human GIRK1 and GIRK4 expression vectors by using Lipofectamine 2000 (produced by Invitrogen Corporation) according to the protocol enclosed with the reagent or using an electronic induction method (“Nucleofector Kit-T”, produced by Amaxa). First, the cells transfected with the GIRK4 expression vector were cultured in a 10% serum-containing F12 medium (produced by Sigma) supplemented with 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. Then the cells expressing GIRK4 were transfected with the GIRK1 expression vector and were cultured in 10% serum-containing F12 medium supplemented with 350 μg/ml of G418 and 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. to select GIRK1/4 expressing cell lines. Cell populations whose growth was observed after about 2 weeks were isolated using cloning rings, and the obtained single colonies were proliferated. RNA was extracted from single colonies, and single-stranded cDNA was synthesized by a cDNA synthesis kit (produced by Invitrogen Corporation), and the amount of expression was quantified at the mRNA level by real-time PCR (Applied Biosystems, Ltd.). Finally, the expressed current was analyzed by patch clamp method described below. The cell lines expressing a current of 500 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamping method.

(3) Measurement of Ion Channel Current by Patch Clamp Method (Human Kv1.5-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolated table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human Kv1.5-expressing cells were cultured was placed in the perfusion chamber.

Depolarizing stimulation pulses were applied and ionic current was recorded by using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, produced by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, produced by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.

The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

NaCl 140 mM, KCl 40 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES 5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.

The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂ creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(4) Measurement of Ion Channel Current by Patch Clamp Method (Human GIRK1/4-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolation table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human GIRK1/4-expressing cells were cultured was placed in the perfusion chamber.

Hyperpolarizing stimulation pulses were applied and ionic current was recorded using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, manufactured by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, manufactured by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.

The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

NaCl 140 mM, KCl 4 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES 5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.

The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂ creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(5) Measurement of Human Kv1.5 Current

While the membrane potential was holded at −80 mV, depolarizing pulses (−80 mV for 0.05 seconds→□□+40 mV for 0.2 seconds→□□−40 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure Kv1.5 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and holding the membrane potential at −80 mV, depolarizing pulses were applied. The current obtained during the pulse application was recorded as a current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and holding the membrane potential at −80 mV, depolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration was recorded.

The data was analyzed by using the step end current recorded during the +40 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the +40 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)

(6) Measurement of Human GIRK1/4 Current

While the membrane potential was holded at −80 mV, hyperpolarizing pulses (−80 mV for 0.05 seconds→□□−120 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure GIRK1/4 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. The current obtained during the pulse application was recorded as the current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration were recorded.

The data was analyzed by using the step end current recorded during the −120 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the −120 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)

(7) Calculation of Inhibitory Activity on Kv1.5 Channel Ionic Current and GIRK1/4 Channel Current

The concentration for 50% inhibition of Kv1.5 channel current or GIRK1/4 channel current (IC₅₀ value) was calculated according to the following nonlinear regression equation:

Relative current=1/(1+[Concentration of the compound]/IC₅₀)^(nH)

wherein nH is the Hill coefficient.

Table 2 shows the test results.

TABLE 2 Test Compound KV1.5 IC₅₀ (μM) Compound of Example 10 0.62 Compound of Example 15 0.81 Compound of Example 16 0.51 Compound of Example 18 0.60 Compound of Example 35 0.94 Compound of Example 41 6.30 Compound of Example 42 1.70 Compound of Example 43 0.32 Compound of Example 48 0.30 Compound of Example 104 1.4 Compound of Example 317 0.63 Compound of Example 318 2.9 Compound of Example 330 0.86

2. Second Invention Reference Example 1 Synthesis of 6-hydroxy-2H-isoquinolin-1-one

A 1.0 M boron tribromide/dichloromethane solution (8.5 ml) was added at 0° C. to a dichloromethane solution (50 ml) of 6-methoxy-2H-isoquinolin-1-one (1.0 g). The mixture was stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction was carried out with a dichloromethane/methanol mixed solvent (dichloromethane:methanol=10:1). The organic layer was dried with anhydrous sodium sulfate, followed by condensation to dryness under reduced pressure, thereby obtaining the title compound (0.4 g) as a pale yellow solid.

¹H NMR (DMSO-d₆), δppm: 6.37 (1H, d, J=7.1 Hz), 6.86-6.94 (2H, m), 7.03-7.08 (1H, m), 8.02 (1H, d, J=8.7 Hz), 10.22 (1H, br), 10.90 (1H, s).

Reference Example 2 Synthesis of 6-hydroxy-1,3-dimethyl-3,4-dihydro-1H-quinazolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 2.87 (3H, s), 3.13 (3H, s), 4.26 (2H, s), 6.57 (1H, d, J=2.7 Hz), 6.65 (1H, dd, J=2.7, 8.7 Hz), 6.73 (1H, d, J=8.7 Hz), 9.13 (1H, s).

Reference Example 3 Synthesis of 6-hydroxy-1,3-dimethyl-1H-quinazoline-2,4-dione

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 3.29 (3H, s), 3.48 (3H, s), 7.20 (1H, dd, J=2.8, 9.0 Hz), 7.31 (1H, d, J=9.0 Hz), 7.40 (1H, d, J=2.8 Hz), 9.76 (1H, s).

Reference Example 4 Synthesis of 6-hydroxy-2-methyl-2H-isoquinolin-1-one

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 3.44 (3H, s), 6.43 (1H, d, J=7.4 Hz), 6.86 (1H, d, J=2.2 Hz), 6.93 (1H, dd, J=8.7, 2.2 Hz), 7.35 (1H, d, J=7.4 Hz), 8.04 (1H, d, J=8.7 Hz).

Reference Example 5 Synthesis of 6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (CDCl₃), δppm: 2.95 (2H, t, J=6.7 Hz), 3.13 (3H, s), 3.57 (2H, t, J=6.7 Hz), 6.62 (1H, d, J=2.4 Hz), 6.76 (1H, dd, J=8.6, 2.4 Hz), 7.83 (1H, d, J=8.6 Hz).

Reference Example 6 Synthesis of 2-methyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-5-ol

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (CDCl₃), δppm: 2.92 (3H, s), 4.24 (2H, s), 6.75 (1H, s), 6.92 (1H, d, J=8.5 Hz), 7.60 (1H, d, J=8.5 Hz).

Reference Example 7 Synthesis of 3-hydroxy-7,8-dihydro-6H-5-thia-8-azabenzocyclohepten-9-one

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (CD₃OD), δppm: 3.15 (2H, t, J=6.0 Hz), 3.21-3.40 (2H, m), 6.84 (1H, dd, J=8.4, 2.4 Hz), 6.96 (1H, d, J=2.4 Hz), 7.46 (1H, d, J=8.4 Hz).

Reference Example 8 Synthesis of 3-hydroxy-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

¹H-NMR (DMSO-d₆), δppm: 3.70 (3H, s), 7.12 (1H, s), 7.17-7.28 (1H, m), 7.35-7.50 (2H, m), 7.56 (1H, d-d, J=1.3, 7.5 Hz), 9.46 (1H, br-s).

Reference Example 9 Synthesis of 7-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one

7-(3-Chloropropoxy)-1-methyl-1H-quinolin-2-one (2.5 g) and sodium iodide (3.0 g) were added to 30 ml of acetonitrile. The mixture was stirred for 18 hours while heated under reflux. After cooled to room temperature, water was added to the reaction mixture, followed by extration using dichloromethane. The organic layer was dried with sodium sulfate and was condensed under reduced pressure to give the title compound (2.4 g) as a pale brown powder.

¹H-NMR (CDCl₃), δppm: 2.29-2.37 (2H, m), 3.41 (2H, t, J=6.6 Hz), 3.69 (3H, s), 4.17 (2H, t, J=5.8 Hz), 6.56 (1H, d, J=9.4 Hz), 6.81-6.84 (2H, m), 7.45-7.58 (1H, m), 7.60 (1H, d, J=9.4 Hz).

Reference Example 10 Synthesis of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one

Sodium hydride (60% in oil, 440 mg) was suspended in DMF (20 ml), and was cooled to 0° C. in ice water bath.

6-(5-Bromopentyloxy)-1H-quinolin-2-one (3.1 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Methyl iodide (1.9 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (2.68 g) as a yellow powder.

¹H-NMR (CDCl₃), δppm: 1.53-1.70 (2H, m), 1.81-1.97 (4H, m), 3.45 (2H, t, J=6.7 Hz), 3.71 (3H, s), 4.00-4.04 (2H, m), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=3.0 Hz), 7.16-7.20 (1H, m), 7.27-7.31 (1H, m), 7.59 (1H, d, J=9.5 Hz).

Reference Example 11 Synthesis of 6-(8-bromooctyloxy)-2-methoxyquinoline

Sodium hydride (60% in oil, 40 mg) was suspended in DMF (2 ml), and was cooled to 0° C. in ice water bath.

6-Hydroxy-2-methoxyquinoline (171 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. 1,8-Dibromooctane (0.37 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (225 mg) as a white powder.

¹H-NMR (CDCl₃), δppm: 1.37-1.51 (8H, m), 1.81-1.89 (4H, m), 3.41 (2H, t, J=6.8 Hz), 4.04 (3H, s), 4.04 (2H, t, J=6.5 Hz), 6.87 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=2.8 Hz), 7.27 (1H, dd, J=9.1, 2.8 Hz), 7.75 (1H, d, J=9.1 Hz), 7.87 (1H, d J=8.8 Hz).

Reference Example 12 Synthesis of 6-(5-bromopentyloxy)-2-methoxyquinoline

The synthesis of the title compound was performed in the same manner as in Reference Example 11 using appropriate starting materials.

¹H-NMR (CDCl₃), δppm: 1.61-1.66 (2H, m), 1.821-1.96 (4H, m), 3.45 (2H, t, J=6.7 Hz), 3.47 (3H, s), 4.00-4.04 (2H, m), 6.70 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).

Reference Example 13 Synthesis of 5-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.

¹H-NMR (CDCl₃), δppm: 2.30-2.44 (2H, m), 3.42 (2H, t, J=6.7 Hz), 3.71 (3H, s), 4.19 (2H, t, J=5.8 Hz), 6.66 (1H, d, J=9.7 Hz), 6.70 (1H, d, J=8.1 Hz), 6.97 (1H, d, J=8.6 Hz), 7.48 (1H, dd, J=8.6, 8.1 Hz), 8.11 (1H, d, J=9.7 Hz).

Reference Example 14 Synthesis of 8-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.

¹H-NMR (CDCl₃), δppm: 2.32-2.40 (2H, m), 3.39 (2H, t, J=6.6 Hz), 3.96 (3H, s), 4.15 (2H, t, J=5.9 Hz), 6.70 (1H, d, J=9.4 Hz), 7.08-7.17 (3H, m), 7.60 (1H, d, J=9.4 Hz).

Reference Example 15 Synthesis of (2-pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine

4-Pyridine carbaldehyde (5.36 g) and 3-(2-aminoethyl)pyridine (6.5 ml) were added to 100 ml of methanol. The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (2.8 g) was added thereto. The mixture was further stirred at 0° C. for an hour. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5→85:5). The purified product was condensed under reduced pressure to give the title compound (10.03 g) as a colorless oily matter.

¹H-NMR (CDCl₃), δppm: 2.79-2.98 (4H, m), 3.82 (2H, s), 7.21 (2H, d, J=5.8 Hz), 7.20-7.27 (1H, m), 7.50-7.56 (1H, m), 8.48 (1H, dd, J=6.7, 1.6 Hz), 8.49 (1H, s), 8.51-8.57 (2H, m).

Reference Example 16 Synthesis of (2-pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-[3-(tetrahydro-pyran-2-yloxy)-propyl]-amine

Sodium iodide (1.5 g) was added to a DMF solution (20 ml) of 2-(3-bromopropoxy)tetrahydropyran (0.85 ml). The mixture was stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature. (2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (1.28 g), and N-ethyldiisopropylamine (1.3 ml) were added thereto. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound (236 mg) as a colorless oily matter.

¹H-NMR (CDCl₃), δppm: 1.40-1.90 (7H, m), 2.51-2.83 (6H, m), 3.29-3.44 (1H, m), 3.44-3.54 (2H, m), 3.54-3.70 (2H, m), 3.69-3.90 (2H, m), 4.47-4.57 (1H, m), 7.12-7.23 (3H, m), 7.37-7.48 (1H, m), 8.38-8.53 (4H, m).

Reference Example 17 Synthesis of 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol

A 2N-hydrogen chloride methanol solution (1.2 ml) was added to a methanol solution (4 ml) of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amine (236 mg). The mixture was stirred at room temperature overnight. A 2N-hydrogen chloride methanol solution (0.5 ml) was added thereto, and the mixture was further stirred at 50° C. for 3 hours. Triethylamine (0.64 ml) was added to the reaction mixture, and the mixture was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane). The purified product was condensed under reduced pressure to give the title compound (186.3 mg) as an orange oily matter.

¹H NMR (CDCl₃), δppm: 1.66-1.88 (2H, m), 2.59-2.77 (4H, m), 2.77-2.88 (2H, m), 3.65 (2H, s), 3.68-3.84 (3H, m), 7.11-7.25 (3H, m), 7.42 (1H, d, J=7.8 Hz), 8.42 (1H, s), 8.43-8.47 (1H, m), 8.50-8.60 (2H, m).

Reference Example 18 Synthesis of (3-chloropropyl)-(2-pyridin-3-ylethyl)pyridin-4-ylmethylamine

(2-Pyridin-3-yl-ethyl)-pyridin-4-ylmethyl-amine (210 mg) and N-ethyldiisopropylamine (0.34 ml) were added to a DMF solution (2 ml) of 1-chloro-3-iodopropane (0.16 ml). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed under reduced pressure to give the title compound (74 mg) as a colorless oily matter.

¹H-NMR (CDCl₃), δppm: 1.82-1.99 (2H, m), 2.61-2.82 (6H, m), 3.52 (2H, t, J=6.3 Hz), 3.61 (2H, s), 7.14 (2H, d, J=5.9 Hz), 7.19 (1H, dd, J=7.7, 4.8 Hz), 7.36-7.49 (1H, m), 8.38-8.56 (4H, m).

Reference Example 19 Synthesis of 2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide

2-Nitrobenzene sulfonyl chloride (11.64 g) was added to a dichloromethane solution (100 ml) of 3-(2-aminoethyl)pyridine (6.11 g) and triethylamine (9 ml) at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (5.06 g) as a yellow powder.

¹H NMR (DMSO-d₆), δppm: 2.76 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 7.26 (1H, dd, J=4.8 Hz, 7.8 Hz), 7.60 (1H, d, J=7.8 Hz), 7.8-8.0 (4H, m), 8.19 (1H, brs), 8.3-8.4 (2H, m).

Reference Example 20 Synthesis of (2-methylbenzyl)-(2-pyridin-3-ylethyl)amine

The synthesis of the title compound was performed in the same manner as in Reference Example 15 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.95-1.95 (1H, br-s), 2.30 (3H, s), 2.77-2.88 (2H, m), 2.91-3.02 (2H, m), 3.78 (2H, s), 7.06-7.30 (5H, m), 7.53 (1H, br-d, J=7.5 Hz), 8.41-8.53 (2H, m).

Reference Example 21 Synthesis of 6-(3-chloropropoxy)-1-methyl-1H-quinolin-2-one

Potassium carbonate (0.829 g) was dissolved in acetonitrile (10 ml) and water (10 ml), and 6-hydroxy-2-methoxyquinoline (0.875 g) and 1-chloro-3-bromopropane (1.48 ml) was added thereto, and the mixture was stirred while heating under reflux for 4 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (1.107 g) as a white powder.

1H-NMR (CDCl3) δppm: 2.18-2.35 (2H, m), 3.71 (3H, s), 3.78 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=5.9 Hz), 6.72 (1H, d, J=9.5 Hz), 7.03 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).

Reference Example 22 Synthesis of 6-(3-aminopropoxy)-1-methyl-1H-quinolin-2-one

Hydrazine hydrate (6.54 ml) was added to a ethanol solution (250 ml) of 2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]isoindole-1,3-dione (16.28 g), and stirred while heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. A 1N-sodium hydroxide aqueous solution was added to the residue, and stirred for 30 minutes, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.04 g) as a colorless oil.

1H-NMR (CDCl3) δppm: 1.89-2.06 (2H, m), 2.95 (2H, t, J=6.8 Hz), 3.71 (3H, s), 4.11 (2H, t, J=6.1 Hz), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).

Reference Example 23 Synthesis of 6-(2-iodoethoxy)-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 3.45 (2H, t, J=6.6 Hz), 3.71 (3H, s), 4.31 (2H, t, J=6.6 Hz), 6.73 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.31 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).

Reference Example 24 Synthesis of 6-(2-aminoethoxy)-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 22 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 3.13 (2H, t, J=5.1 Hz), 3.71 (3H, s), 4.05 (2H, t, J=5.1 Hz), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.31 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=9.5 Hz).

Reference Example 25 Synthesis of 2-nitro-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzene sulfonamide

The synthesis of the title compound was performed in the same manner as in Reference Example 19 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.42-1.99 (4H, m), 2.13-2.35 (2H, m), 2.43-2.69 (4H, m), 3.21 (2H, t, J=6.0 Hz), 3.39-3.54 (1H, m), 4.52 (2H, s), 7.28 (1H, dd, J=7.9, 4.8 Hz), 7.63-7.70 (1H, m), 7.70-7.79 (2H, m), 7.83-7.89 (1H, m), 8.91-8.98 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz), 8.56 (1H, d, J=1.6 Hz).

Reference Example 26 Synthesis of 6-(4-aminobutoxy)-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 22 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.58-1.72 (2H, m), 1.81-1.98 (2H, m), 2.80 (2H, t, J=6.9 Hz), 3.71 (3H, s), 4.03 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).

Reference Example 27 Synthesis of 6-(3-iodopropoxy)-1-methyl-3,4-dihydro-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 2.16-2.32 (2H, m), 2.56-2.70 (2H, m), 2.87 (2H, t, J=6.7 Hz), 3.33 (3H, s), 3.31-3.45 (2H, m), 4.02 (2H, t, J=5.8 Hz), 6.75 (1H, d, J=2.8 Hz), 6.78 (1H, dd, J=8.7, 2.8 Hz), 6.89 (1H, d, J=8.7 Hz).

Reference Example 28 Synthesis of N-(3-imidazol-1-yl-propyl)-2-nitrobenzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Reference Example 19 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.71-1.95 (2H, m), 2.85 (2H, t, J=6.8 Hz), 3.97 (2H, t, J=6.9 Hz), 6.86 (1H, s), 7.10 (1H, s), 7.55 (1H, s), 7.83-7.92 (2H, m), 7.92-8.02 (2H, m), 8.16 (1H, s).

Reference Example 30 Synthesis of N-(3-Chloropropyl)-N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amine

The synthesis of the title compound was performed in the same manner as in Reference Example 18 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.78-1.95 (2H, m), 2.26 (3H, s), 2.60-2.79 (6H, m), 3.50 (2H, t, J=6.5 Hz), 3.58 (2H, s), 7.08-7.24 (5H, m), 7.33-7.39 (1H, m), 8.36 (1H, d, J=1.7 Hz), 8.41 (1H, dd, J=4.8, 1.7 Hz).

Reference Example 31 Synthesis of 6-(3-iodopropoxy)-3,4-dihydro-2H-isoquinolin-1-one

The synthesis of the title compound was performed in the same manner as in Reference Example 9 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 2.19-2.35 (2H, m), 2.97 (2H, t, J=6.6 Hz), 3.37 (2H, t, J=6.7 Hz), 3.50-3.62 (2H, m), 4.09 (2H, t, J=5.8 Hz), 5.98 (1H, s), 6.71 (1H, d, J=2.4 Hz), 6.86 (1H, dd, J=8.6, 2.4 Hz), 8.01 (1H, d, J=8.6 Hz).

Reference Example 32 Synthesis of 2-hydroxy-7,8-dihydro-6H-5-thia-8-aza-benzocyclohepten-9-one

The synthesis of the title compound was performed in the same manner as in Reference Example 1 using appropriate starting materials.

1H-NMR (CD3OD) δppm: 3.06 (2H, t, J=6.0 Hz), 3.26 (2H, t, J=6.0 Hz), 6.85 (1H, dd, J=8.3, 2.8 Hz), 7.01 (1H, d, J=2.8 Hz), 7.34 (1H, d, J=8.3 Hz).

Example 1 Synthesis of 1-methyl-6-{5-[(2-methylbenzyl)-(2-pyridin-3-ylethyl)amino]pentyl oxy}-1H-quinolin-2-one dihydrochloride

Potassium carbonate (360 mg) and (2-methylbenzyl)-(2-pyridin-3-ylethyl)amine (591 mg) were added to a DMF solution (6.5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one (650 mg). The mixture was stirred at 60° C. for 8 hours. Ice water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate:methanol:aqueous ammonia=70:20:10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound (270 mg) as a pale yellow amorphus solid.

¹H-NMR (DMSO-d₆) δppm: 1.32-1.50 (2H, m), 1.65-1.99 (4H, m), 2.47 (3H, s), 2.92-3.21 (2H, m), 3.21-3.50 (4H, m), 3.59 (3H, s), 3.88-4.09 (2H, m), 4.30-4.52 (2H, m), 6.61 (1H, d, J=9.4 Hz), 7.05-7.35 (5H, m), 7.46 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=7.2 Hz), 7.84 (1H, d, J=9.6 Hz), 7.89-8.01 (1H, m), 8.40 (1H, br-d, J=7.8 Hz), 8.79 (1H, d, J=4.9 Hz), 8.89 (1H, s).

Example 2 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide

2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (308 mg), and potassium carbonate (276 mg) were added to a DMF solution (5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one (348 mg). The mixture was stirred at room temperature for 2 hours. Ice water was poured to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1). The purified product was condensed to dryness under reduced pressure to give 5 the title compound (535 mg) as a yellow amorphus solid.

¹H-NMR (CDCl₃) δppm: 1.4-1.9 (6H, m), 2.88 (2H, t, J=7.5 Hz), 3.40 (2H, t, J=7.5 Hz), 3.52 (2H, t, J=7.7 Hz), 3.71 (3H, s), 3.98 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.1-7.3 (2H, m), 7.29 (1H, d, J=9.2 Hz), 7.4-7.7 (5H, m), 7.9-8.1 (1H, m), 8.40 (1H, d, J=1.8 Hz), 8.45 (1H, dd, J=1.8 Hz, 4.8 Hz).

Example 3 Synthesis of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride

Lithium hydroxide (102 mg), and thioglycolic acid (0.141 ml) were added to a DMF solution (5 ml) of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (535 mg). The mixture was stirred at room temperature overnight. Ice water was poured to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (1.0 ml), and ethyl acetate were added to the residue. The mixture was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (108 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 1.4-1.6 (2H, m), 1.6-1.8 (4H, m), 2.8-3.0 (2H, m), 3.2-3.4 (4H, m), 3.60 (3H, s), 4.04 (2H, t, J=6.1 Hz), 4.0-4.8 (1H, br), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.31 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.05 (1H, dd, J=5.6 Hz, 8.1 Hz), 8.57 (1H, d, J=8.1 Hz), 8.84 (1H, d, J=5.6 Hz), 8.94 (1H, s), 9.36 (1H, brs).

Example 4 Synthesis of 1-methyl-6-[5-((2-methylbenzyl)-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}amino)pentyloxy]-1H-quinolin-2-one trihydrochloride

Methane sulfonyl chloride (0.59 ml) was added to a dichloromethane solution (30 ml) of 6-{5-[(2-hydroxyethyl)-(2-methylbenzyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one (2.83 g) and N-ethyldiisopropylamine (1.81 ml). The mixture was stirred at room temperature for an hour. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was dissolved in acetonitrile (50 ml). Sodium iodide (1.56 g), 3-(piperidin-4-yloxymethyl)pyridine (1.46 g) and N-ethyldiisopropylamine (3.61 ml) were added thereto, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate:methanol:aqueous ammonia=70:20:10:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.41 ml) was added to an isopropyl alcohol solution of the residue. The mixture was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound (2.41 g) as a white amorphous solid.

¹H-NMR (DMSO-d₆) δppm: 1.4-1.6 (2H, m), 1.7-2.3 (8H, m), 2.46 (3H, s), 3.0-3.9 (11H, m), 3.60 (3H, s), 4.02 (2H, t, J=6.2 Hz), 4.46 (2H, s), 4.75 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.2-7.4 (5H, m), 7.47 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=9.5 Hz), 8.04 (1H, dd, J=5.7 Hz, 8.0 Hz), 8.5-8.6 (1H, br), 8.85 (1H, d, J=5.7 Hz), 8.94 (1H, brs), 10.2-11.8 (2H, br).

Example 5 Synthesis of 6-{5-[cyclohexylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

Triethylamine (0.15 ml) was added to a 1,2-dichloroethane solution (2.5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride (219 mg). The mixture was stirred at room temperature for 30 minutes. Cyclohexane carboxaldehyde (0.073 ml) and sodium triacetoxyborohydrate (159 mg) were added thereto, and the mixture was stirred at room temperature overnight. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (1.0 ml) was added to an ethanol solution (20 ml) of the residue, which was stirred at room temperature. The reaction mixture was condensed under reduced pressure and ethyl acetate was added to the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (100 mg) as a pale yellow powder.

¹H-NMR (DMSO-d₆) δppm: 0.8-1.4 (6H, m), 1.5-2.0 (11H, m), 2.9-3.6 (8H, m), 3.59 (3H, s), 4.0-4.5 (1H, br), 4.06 (2H, t, J=6.1 Hz), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.31 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=5.6 Hz, 8.1 Hz), 8.53 (1H, J=8.1 Hz), 8.83 (1H, d, J=5.6 Hz), 8.95 (1H, s), 10.4 (1H, brs).

Example 6 Synthesis of 6-{5-[(2,6-dichlorobenzyl)-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.3-1.6 (2H, m), 1.7-2.0 (4H, m), 3.0-3.7 (8H, m), 3.58 (3H, s), 4.02 (2H, t, J=6.0 Hz), 4.0-5.0 (1H, br), 6.59 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=2.8 Hz, 9.1 Hz), 7.27 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.1 Hz), 7.4-7.7 (3H, m), 7.82 (1H, d, J=9.5 Hz), 7.8-8.0 (1H, m), 8.38 (1H, d, J=7.7 Hz), 8.76 (1H, d, J=5.3 Hz), 9.02 (1H, s), 9.9-10.2 (1H, br).

Example 7 Synthesis of 6-{5-[isobutyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

Example 8 Synthesis of 6-{5-[cyclohexyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

Example 9 Synthesis of 6-{5-[benzyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.3-1.5 (2H, m), 1.7-2.0 (4H, m), 3.0-3.2 (2H, m), 3.3-3.5 (4H, m), 3.59 (3H, s), 4.03 (2H, t, J=6.2 Hz), 4.3-4.6 (2H, m), 4.0-4.5 (1H, br), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=2.8 Hz, 9.1 Hz), 7.29 (1H, d, J=2.8 Hz), 7.4-7.5 (4H, m), 7.6-7.8 (2H, m), 7.83 (1H, d, J=9.5 Hz), 7.90 (1H, dd, J=5.3 Hz, 8.1 Hz), 8.35 (1H, d, J=8.1 Hz), 8.78 (1H, d, J=5.3 Hz), 8.85 (1H, s), 11.22 (1H, brs).

Example 10 Synthesis of 1-methyl-6-{5-[(2-pyridin-3-ylethyl)-o-tolylamino]pentyloxy}-1H-quinolin-2-one dihydrochloride

1-Methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (183 mg), 2-bromotoluene (0.072 ml), palladium acetate (II)(5.6 mg), tri-tert-butylphosphine tetrafluoroborate (8 mg), and sodium t-butoxide (0.19 ml) were added to toluene (1 ml). The mixture was heated under reflux for 8 hours under nitrogen atmosphere. After the reaction, the precipitate was removed from the reaction mixture by celite filtration. Water was added thereto, followed by extraction using dichloromethane. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=20:1). The purified product was condensed under reduced pressure to give the title compound (93 mg) as a yellow oily matter.

¹H-NMR (DMSO-d₆) δppm: 1.2-1.5 (2H, m), 1.6-1.9 (2H, m), 2.0-2.2 (2H, m), 2.50 (3H, s), 2.7-3.5 (6H, m), 3.59 (3H, s), 3.96 (2H, t, J=6.3 Hz), 4.0-5.0 (2H, br), 6.59 (1H, d, J=9.5 Hz), 7.0-7.4 (6H, m), 7.44 (1H, d, J=9.1 Hz), 7.82 (1H, d, J=9.5 Hz), 7.9-8.0 (1H, m), 8.3-8.4 (1H, m), 8.7-8.8 (2H, m).

Example 11 Synthesis of 1-methyl-6-{5-[(3-phenylpropyl)-(2-pyridin-3-ylethyl)amino]pentyl oxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.3-1.5 (2H, m), 1.6-1.9 (4H, m), 2.0-2.2 (2H, m), 2.63 (2H, t, J=7.7 Hz), 3.0-3.5 (8H, m), 3.59 (3H, s), 3.8-4.2 (3H, m), 6.60 (1H, d, J=9.5 Hz), 7.1-7.4 (7H, m), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.97 (1H, dd, J=5.3 Hz, 8.1 Hz), 8.48 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=5.3 Hz), 8.92 (1H, s), 11.04 (1H, brs).

Example 12 Synthesis of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.3-1.5 (2H, m), 1.6-1.9 (4H, m), 3.0-3.2 (2H, m), 3.2-3.5 (4H, m), 3.58 (3H, s), 3.85 (3H, s), 4.00 (2H, t, J=6.3 Hz), 4.3-4.6 (2H, m), 4.5-5.5 (1H, br), 6.59 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.27 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 7.86 (2H, d, J=8.3 Hz), 7.9-8.0 (1H, m), 7.99 (2H, d, J=8.3 Hz), 8.42 (1H, d, J=8.2 Hz), 8.79 (1H, d, J=5.5 Hz), 8.88 (1H, s), 11.50 (1H, brs).

Example 13 Synthesis of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid

A 1N-sodium hydroxide aqueous solution (0.72 ml) was added to a methanol solution (2 ml) of 4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester (153 mg). The mixture was stirred at 50° C. for 3 hours. The reaction mixture was condensed under reduced pressure. Water was added to the residue, and acetic acid was added for neutralization. The mixture was extracted using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. Diisopropyl ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (115 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 1.2-1.5 (4H, m), 1.6-1.8 (2H, m), 2.3-2.6 (2H, m), 2.6-2.8 (4H, m), 3.59 (3H, s), 3.67 (2H, s), 3.96 (2H, t, J=6.4 Hz), 6.59 (1H, d, J=9.5 Hz), 7.1-7.3 (3H, m), 7.33 (2H, d, J=8.2 Hz), 7.44 (1H, d, J=9.1 Hz), 7.5-7.6 (1H, m), 7.7-7.9 (3H, m), 8.1-8.3 (2H, m), 12.5-13.0 (1H, br).

Example 14 Synthesis of 1-methyl-6-{5-[(2-methylbenzyl)pyridin-3-ylmethylamino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.3-1.5 (2H, m), 1.6-1.8 (2H, m), 1.8-2.0 (2H, m), 2.35 (3H, s), 3.0-3.2 (2H, m), 3.60 (3H, s), 3.9-4.1 (2H, m), 4.2-5.7 (5H, m), 6.61 (1H, d, J=9.5 Hz), 7.1-7.4 (5H, m), 7.46 (1H, d, J=9.2 Hz), 7.75 (1H, d, J=7.3 Hz), 7.85 (1H, d, J=9.5 Hz), 7.99 (1H, dd, J=5.4 Hz, 7.9 Hz), 8.85 (1H, d, J=7.9 Hz), 8.91 (1H, d, J=5.4 Hz), 9.21 (1H, s), 11.64 (1H, brs).

Example 15 Synthesis of 1-methyl-6-{5-[(3-phenylpropyl)pyridin-3-ylmethylamino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.3-1.5 (2H, m), 1.6-1.9 (4H, m), 1.9-2.2 (2H, m), 2.61 (2H, t, J=7.5 Hz), 2.9-3.2 (4H, m), 3.59 (3H, s), 4.02 (2H, t, J=6.2 Hz), 4.0-5.0 (3H, m), 6.61 (1H, d, J=9.5 Hz), 7.1-7.4 (7H, m), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 7.9-8.1 (1H, m), 8.77 (1H, d, J=7.9 Hz), 8.92 (1H, d, J=5.0 Hz), 9.18 (1H, s), 11.71 (1H, brs).

Example 16 Synthesis of 6-[5-(bis{pyridin-3-ylmethyl}amino)pentyloxy]-1-methyl-1H-quinolin-2-one

Pyridine-3-carbaldehyde (0.076 ml) was added to a 1,2-dichloroethane solution (3 ml) of 1-methyl-6-{5-[(pyridin-3-ylmethyl)-amino]-pentyloxy}-1H-quinolin-2-one (237 mg). The mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature for 3 days. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1). The purified product was condensed under reduced pressure to give the title compound (247 mg) as a yellow oil.

¹H-NMR (CDCl₃) δppm: 1.3-1.8 (6H, m), 2.47 (2H, t, J=6.8 Hz), 3.58 (4H, s), 3.71 (3H, s), 3.95 (2H, t, J=6.4 Hz), 6.70 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.2-7.4 (3H, m), 7.60 (1H, d, J=9.5 Hz), 7.6-7.7 (2H, m), 8.49 (2H, dd, J=1.6 Hz, 4.8 Hz), 8.57 (2H, d, J=1.7 Hz).

Example 17 Synthesis of 1-methyl-6-{5-[(2-methylbenzyl)pyridin-3-ylamino]pentyloxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 1.5-1.7 (2H, m), 1.8-1.9 (4H, m), 2.32 (3H, s), 3.45 (2H, t, J=7.6 Hz), 3.71 (3H, s), 4.01 (2H, t, J=6.3 Hz), 4.46 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.8-6.9 (1H, m), 6.98 (1H, d, J=2.8 Hz), 7.0-7.3 (6H, m), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz), 7.92 (1H, dd, J=1.2 Hz, 4.6 Hz), 8.09 (1H, d, J=3.0 Hz).

Example 18 Synthesis of 1-methyl-6-{5-[(3-phenylpropyl)pyridin-3-ylamino]pentyloxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 1.4-1.7 (4H, m), 1.8-2.1 (4H, m), 2.66 (2H, t, J=7.7 Hz), 3.2-3.4 (4H, m), 3.70 (3H, s), 4.00 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 6.8-6.9 (1H, m), 6.98 (1H, d, J=2.8 Hz), 7.05 (1H, dd, J=4.6 Hz, 8.6 Hz), 7.1-7.4 (7H, m), 7.58 (1H, d, J=9.5 Hz), 7.88 (1H, dd, J=1.2 Hz, 4.5 Hz), 8.04 (1H, d, J=3.0 Hz).

Example 19 Synthesis of 1-methyl-6-{5-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]pentyloxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆)₆ ppm: 0.80-2.02 (6H, m), 3.05-3.25 (2H, m), 3.36-3.52 (4H, m), 3.60 (3H, s), 3.97-4.10 (2H, m), 4.82 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.1, 2.8 Hz), 7.32 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.86 (1H, d, J=9.5 Hz), 8.06 (1H, dd, J=8.1, 5.7 Hz), 8.53 (2H, d, J=6.3 Hz), 8.59 (1H, d, J=8.1 Hz), 8.86 (1H, d, J=5.7 Hz), 8.88 (1H, s), 9.04 (2H, d, J=6.3 Hz).

Example 20 Synthesis of 1-Methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]ethoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δ: 2.78-2.91 (4H, m), 3.00 (2H, t, J=5.6 Hz), 3.69 (3H, s), 3.79 (2H, s), 4.04 (2H, t, J=5.6 Hz), 6.70 (1H, d, J=9.5 Hz), 6.63 (1H, d, J=2.8 Hz), 7.15-7.30 (4H, m), 7.41-7.50 (1H, m), 7.57-7.60 (2H, m), 8.42-8.53 (4H, m).

Example 21 Synthesis of 1-methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]ethoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 2.79-2.91 (4H, m), 3.01 (2H, t, J=5.6 Hz), 3.70 (3H, s), 3.79 (2H, s), 4.05 (2H, t, J=5.6 Hz), 6.71 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.11-7.20 (4H, m), 7.27-7.30 (1H, m), 7.41-7.48 (1H, m), 7.58 (1H, d, J=9.5 Hz), 8.43-8.49 (4H, m).

Example 22 Synthesis of 1-methyl-6-[3-(pyridin-4-ylmethylpyridin-3-ylmethylamino)propoxy]-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.86-2.19 (2H, m), 3.61 (3H, s), 3.71-5.00 (8H, m), 6.62 (1H, d, J=9.5 Hz), 7.09 (1H, dd, J=9.2, 2.8 Hz), 7.20 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.80-7.94 (1H, m), 8.02-8.12 (2H, m), 8.52 (1H, d, J=7.3 Hz), 8.73-8.83 (3H, m), 8.93 (1H, s).

Example 23 Synthesis of 1-methyl-6-[4-(pyridin-4-ylmethylpyridin-3-ylmethylamino)butoxy]-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.61-1.98 (4H, m), 2.60-3.00 (2H, m), 3.60 (3H, s), 3.23-5.11 (6H, m), 6.61 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.2, 2.9 Hz), 7.24 (1H, d, J=2.9 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.89-8.00 (1H, m), 8.11-8.26 (2H, m), 8.64 (1H, d, J=7.8 Hz), 8.84 (1H, d, J=4.5 Hz), 8.88 (2H, d, J=6.4 Hz), 9.02 (1H, s).

Example 24 Synthesis of 1-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 1.88-1.96 (2H, m), 2.68-2.81 (6H, m), 3.66 (2H, s), 3.71 (3H, s), 3.93 (2H, t, J=6.0 Hz), 6.73 (1H, d, J=9.5 Hz), 6.92 (1H, d, J=2.8 Hz), 7.09-7.16 (4H, m), 7.28-7.31 (1H, m), 7.39-7.46 (1H, m), 7.62 (1H, d, J=9.5 Hz), 8.41-8.46 (4H, m).

Example 25 Synthesis of 1-Methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 1.85-1.91 (2H, m), 2.60-2.88 (10H, m), 3.33 (3H, s), 3.64 (2H, s), 3.88 (2H, t, J=6.0 Hz), 6.64-6.71 (2H, m), 6.89 (1H, d, J=8.7 Hz), 7.13-7.19 (2H, m), 7.30-7.33 (1H, m), 7.35-7.46 (1H, m), 8.40-8.52 (3H, m), 8.53 (1H, d, J=1.2 Hz).

Example 26 Synthesis of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(quinolin-6-yloxy)propyl]amine

The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 1.93-2.02 (2H, m), 2.71-2.80 (6H, m), 3.66 (2H, s), 4.02 (2H, t, J=6.1 Hz), 6.989 (1H, d, J=2.8 Hz), 7.09-7.18 (3H, m), 7.28-7.39 (3H, m), 7.98-8.06 (2H, m), 8.43-8.45 (4H, m), 8.77-8.78 (1H, m).

Example 27 Synthesis of 1-methyl-5-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

(2-Pyridin-3-ylethyl)pyridin-4-ylmethylamine (128 mg), and N-ethyldiisopropylamine (0.13 ml) were added to a DMF solution (5 ml) of 5-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one (172 mg). The mixture was stirred at 60° C. for 3.5 hours. The reaction mixture was added to ice water, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→1:1).

The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration and dried to give the title compound (21 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 2.26-2.54 (2H, m), 3.00-5.29 (10H, m), 3.60 (3H, s), 6.56 (1H, d, J=9.7 Hz), 6.83 (1H, d, J=8.2 Hz), 7.12 (1H, d, J=8.6 Hz), 7.51-7.60 (1H, m), 7.92 (1H, d, J=9.7 Hz), 8.02 (1H, dd, J=8.0, 5.5 Hz), 8.24-8.40 (2H, m), 8.54 (1H, d, J=8.0 Hz), 8.84 (1H, d, J=5.5 Hz), 8.92 (2H, d, J=5.6 Hz), 8.95 (1H, s).

Example 28 Synthesis of 1-methyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.14-2.43 (2H, m), 2.88-4.95 (10H, m), 3.59 (3H, s), 6.44 (1H, d, J=9.4 Hz), 6.85 (1H, d, J=8.6 Hz), 6.89 (1H, s), 7.65 (1H, d, J=8.6 Hz), 7.83 (1H, d, J=9.4 Hz), 7.97 (1H, dd, J=8.0, 5.6 Hz), 8.07-8.24 (2H, m), 8.47 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.6 Hz), 8.86 (2H, d, J=5.6 Hz), 8.90 (1H, s).

Example 29 Synthesis of 1-methyl-8-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.30-2.55 (2H, m), 3.25-3.60 (6H, m), 3.77 (3H, s), 4.09-4.29 (2H, m), 4.54-5.00 (2H, m), 6.60 (1H, d, J=9.4 Hz), 7.16-7.28 (2H, m), 7.31 (1H, dd, J=6.8, 2.3 Hz), 7.84 (1H, d, J=9.4 Hz), 8.04 (1H, dd, J=8.1, 5.4 Hz), 8.32-8.46 (2H, m), 8.56 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.4 Hz), 8.91-9.02 (3H, m).

Example 30 Synthesis of 6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 27 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.18-2.40 (2H, m), 3.15-3.56 (6H, m), 3.95-4.16 (2H, m), 4.59-4.87 (2H, m), 6.51 (1H, d, J=9.5 Hz), 7.12 (1H, dd, J=8.9, 2.7 Hz), 7.20 (1H, d, J=2.7 Hz), 7.28 (1H, d, J=8.9 Hz), 7.86 (1H, d, J=9.5 Hz), 8.03 (1H, dd, J=8.1, 5.4 Hz), 8.31-8.44 (2H, m), 8.55 (1H, d, J=8.1 Hz), 8.84 (1H, d, J=5.4 Hz), 8.93-9.03 (3H, m).

Example 31 Synthesis of 1-methyl-4-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

Triphenyl phosphine (102 mg) and diethyl azodicarboxylate (68 mg) were added to a tetrahydrofuran (THF) solution (5 ml) of 4-hydroxy-1-methyl-1H-quinolin-2-one (63 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propane-1-ol (81.4 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.29 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and dried to give the title compound (126.8 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 2.29-2.56 (2H, m), 3.11-3.61 (6H, m), 3.56 (3H, s), 4.11-4.30 (2H, m), 4.50-4.94 (2H, m), 6.03 (1H, s), 7.32-7.41 (1H, m), 7.52 (1H, d, J=8.4 Hz), 7.62-7.76 (2H, m), 8.10 (1H, dd, J=8.0, 5.3 Hz), 8.21-8.34 (2H, m), 8.53 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.3 Hz), 8.90 (2H, d, J=5.7 Hz), 8.94 (1H, s).

Example 32 Synthesis of 6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-2H-isoquinolin-1-one trihydrochloride

Triphenyl phosphine (51 mg) and di-tert-butyl azodicarboxylate (45 mg) were added to a tetrahydrofuran (THF) solution (1.5 ml) of 6-hydroxy-2H-isoquinolin-1-one (29 mg), and 3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propan-1-ol (40 mg). The mixture was stirred overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.06 ml) was added to an ethyl acetate solution of the residue, which was stirred at room temperature for 30 minutes. The generated insoluble matter was separated by filtration, and was dried to produce the title compound (31.4 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 2.14-2.45 (2H, m), 2.91-3.78 (6H, m), 4.08-4.25 (2H, m), 4.37-4.81 (2H, m), 6.46 (1H, d, J=7.1 Hz), 6.99 (1H, dd, J=8.8, 2.2 Hz), 7.08 (1H, d, J=2.2 Hz), 7.10-7.18 (1H, m), 7.92 (1H, dd, J=8.0, 5.5 Hz), 7.99-8.14 (2H, m), 8.08 (1H, d, J=8.8 Hz), 8.41 (1H, d, J=8.0 Hz), 8.78 (1H, d, J=5.5 Hz), 8.83 (2H, d, J=5.8 Hz), 8.87 (1H, s), 10.98-11.17 (1H, m).

Example 33 Synthesis of 2-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.09-2.41 (2H, m), 2.85-3.44 (6H, m), 3.47 (3H, s), 4.08-4.26 (2H, m), 4.26-4.66 (2H, m), 6.52 (1H, d, J=7.3 Hz), 6.99 (1H, dd, J=8.9, 2.3 Hz), 7.07 (1H, d, J=2.3 Hz), 7.44 (1H, d, J=7.3 Hz), 7.72 (1H, dd, J=7.6, 5.3 Hz), 7.81-7.92 (2H, m), 8.11 (1H, d, J=8.9 Hz), 8.11-8.19 (1H, m), 8.67 (1H, dd, J=5.3, 1.2 Hz), 8.69-8.76 (3H, m).

Example 34 Synthesis of 1,3-dimethyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-1H-quinazolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.08-2.38 (2H, m), 2.88 (3H, s), 3.16 (3H, s), 3.08-3.56 (6H, m), 3.92-4.05 (2H, m), 4.32 (2H, s), 4.42-4.85 (2H, m), 6.73 (1H, br-s), 6.70-6.90 (2H, m), 7.98 (1H, d-d, J=5.5, 8.1 Hz), 8.04-8.28 (2H, m), 8.46 (1H, d, J=8.1 Hz), 8.81 (1H, d, J=5.5 Hz), 8.81-8.98 (3H, m).

Example 35 Synthesis of 6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.13-2.40 (2H, m), 2.86 (2H, t, J=6.5 Hz), 3.10-3.57 (8H, m), 4.00-4.15 (2H, m), 4.55-4.81 (2H, m), 6.74-6.88 (2H, m), 7.66-7.80 (2H, m), 8.01 (1H, d-d, J=5.0, 8.0 Hz), 8.19-8.40 (2H, m), 8.52 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.0 Hz), 8.85-9.00 (3H, m).

Example 36 Synthesis of 5-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-2,3-dihydro-isoindol-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.15-2.43 (2H, m), 3.00-3.58 (6H, m), 3.96-4.16 (2H, m), 4.32 (2H, s), 4.44-4.83 (2H, m), 6.96 (1H, d-d, J=1.9, 8.3 Hz), 7.07 (1H, s), 7.57 (1H, d, J=8.3 Hz), 7.92-8.05 (1H, m), 8.10-8.40 (3H, m), 8.41-8.55 (1H, m), 8.78-9.00 (4H, m).

Example 37 Synthesis of N-ethyl-4-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}benzamide trihydrochloride

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(95 mg), and 1-hydroxy benzotriazole (HOBt)(66 mg) were added to a DMF solution (4 ml) of 4-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}benzoic acid (149 mg), ethyl amine hydrochloride (38 mg), and triethylamine (0.08 ml). The mixture was stirred at room temperature overnight. The reaction mixture was added to ice water. A 1N-sodium hydroxide aqueous solution was added thereto, followed by extraction using ethyl acetate. The organic layer was washed with water and then was dried with anhydrous sodium sulfate, followed by condensation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.16 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (80 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 1.11 (3H, t, J=7.2 Hz), 2.10-2.38 (2H, m), 2.89-3.57 (8H, m), 3.95-4.20 (2H, m), 4.28-4.69 (2H, m), 6.92 (2H, d, J=8.8 Hz), 7.75 (1H, dd, J=7.8, 5.2 Hz), 7.82 (2H, d, J=8.8 Hz), 7.83-7.94 (2H, m), 8.18 (1H, d, J=7.8 Hz), 8.35 (1H, t, J=5.4 Hz), 8.68 (1H, dd, J=5.2, 1.3 Hz), 8.71-8.79 (3H, m).

Example 38 Synthesis of 2-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.10-2.40 (2H, m), 2.74-3.62 (10H, m), 2.99 (3H, s), 3.74-4.20 (2H, m), 4.39-4.82 (2H, m), 6.77 (1H, s), 6.82 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.87-8.00 (1H, m), 8.05-8.22 (2H, m), 8.46 (1H, d, J=8.2 Hz), 8.71-8.92 (4H, m).

Example 39 Synthesis of [3-(2-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yloxy)propyl]-(2-pyridin-3-ylethyl)pyridin-4-ylmethylamine trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.08-2.39 (2H, m), 2.79 (3H, s), 2.88-3.58 (6H, m), 4.00-4.20 (2H, m), 4.29-4.65 (2H, m), 4.35 (2H, s), 7.02-7.11 (2H, m), 7.70-7.81 (2H, m), 7.81-7.93 (2H, m), 8.18 (1H, d, J=8.1 Hz), 8.68 (1H, dd, J=5.2, 1.2 Hz), 8.70-8.79 (3H, m).

Example 40 Synthesis of 1-methyl-6-[3-(phenethylpyridin-4-ylmethylamino)propoxy]-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.10-2.40 (2H, m), 2.79-3.70 (6H, m), 3.60 (3H, s), 3.99-4.19 (2H, m), 4.30-4.61 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.15-7.36 (7H, m), 7.47 (1H, d, J=9.2 Hz), 7.68-7.80 (2H, m), 7.84 (1H, d, J=9.5 Hz), 8.67 (2H, d, J=4.9 Hz).

Example 41 Synthesis of 1-methyl-6-{3-[(2-pyridin-2-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.12-2.31 (2H, m), 3.07-3.29 (2H, m), 3.33-3.59 (4H, m), 3.60 (3H, s), 3.95-4.19 (2H, m), 4.53 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.7 Hz), 7.25 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.2 Hz), 7.58-7.67 (1H, m), 7.72 (1H, d, J=7.9 Hz), 7.85 (1H, d, J=9.5 Hz), 8.04 (2H, d, J=6.2 Hz), 8.11-8.21 (1H, m), 8.67 (1H, d, J=4.7 Hz), 8.80 (2H, d, J=6.2 Hz).

Example 42 Synthesis of N-methyl-N-(2-{[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.15-2.41 (2H, m), 2.95 (3H, s), 3.01-3.51 (4H, m), 3.60 (3H, s), 3.70-4.24 (4H, m), 4.33-4.72 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.18 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.33-7.54 (6H, m), 7.82 (1H, d, J=9.5 Hz), 7.92-8.08 (2H, m), 8.67-8.82 (2H, m).

Example 43 Synthesis of 1-ethyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.19 (3H, t, J=7.0 Hz), 2.18-2.41 (2H, m), 2.94-3.59 (6H, m), 3.96-4.18 (2H, m), 4.25 (2H, q, J=7.0 Hz), 4.35-4.63 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.3, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.52 (1H, d, J=9.3 Hz), 7.61-7.76 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.85-8.00 (2H, m), 8.09-8.20 (1H, m), 8.67 (1H, dd, J=5.3, 1.4 Hz), 8.69-8.80 (3H, m).

Example 44 Synthesis of 1-benzyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.80-2.00 (2H, m), 2.52-2.82 (6H, m), 3.63 (2H, s), 3.78-3.98 (2H, m), 5.54 (2H, s), 6.82 (1H, d, J=9.5 Hz), 6.84-6.99 (2H, m), 7.05-7.44 (10H, m), 7.67 (1H, d, J=9.5 Hz), 8.30-8.52 (4H, m).

Example 45 Synthesis of N-methyl-N-(2-{[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)benzamide dihydrochloride

Benzoyl chloride (0.14 ml) was added to a dichloromethane solution (10 ml) of 6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride (382 mg), and triethylamine (0.56 ml) under ice cooling. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.28 ml) was added to an ethyl acetate solution (10 ml) of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (242 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 2.04-2.36 (2H, m), 2.78-2.92 (2H, m), 2.95 (3H, s), 3.00-3.46 (6H, m), 3.64-3.94 (2H, m), 3.94-4.21 (2H, m), 4.31-4.61 (2H, m), 6.77 (1H, s), 6.81 (1H, d, J=8.5 Hz), 7.29-7.59 (6H, m), 7.78 (1H, d, J=8.5 Hz), 7.91-8.18 (2H, m), 8.78 (2H, d, J=4.9 Hz).

Example 46 Synthesis of 2,3-dihydrobenzofuran-7-carboxylic acid methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)amide dihydrochloride

PS-Carbodiimide resin (1.3 g) and 1-hydroxy benzotriazole (HOBt)(230 mg) were added to acetonitrile and THF solution (4 ml+6 ml) of 1-methyl-6-{3-[(2-methylamino ethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one (304 mg) and 2,3-dihydrobenzofuran-7-carboxylic acid (164 mg). The mixture was stirred at room temperature overnight. After the reaction mixture was filtrated and condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.35 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (324.2 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 2.10-2.44 (2H, m), 2.88-3.45 (6H, m), 2.91 (3H, s), 3.59 (3H, s), 3.70-4.25 (4H, m), 4.31-4.72 (4H, m), 6.58 (1H, d, J=9.5 Hz), 6.75-6.91 (1H, m), 6.91-7.12 (1H, m), 7.12-7.32 (3H, m), 7.43 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 7.98-8.30 (2H, m), 8.69-8.94 (2H, m).

Example 47 Synthesis of 3-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-7,8-dihydro-6H-5-thia-8-aza-benzocyclohepten-9-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.10-2.41 (2H, m), 3.00-3.60 (10H, m), 3.99-4.19 (2H, m), 4.43-4.84 (2H, m), 6.89-7.01 (2H, m), 7.48 (1H, d, J=8.6 Hz), 7.98 (1H, dd, J=8.0, 5.3 Hz), 8.04-8.21 (2H, m), 8.27 (1H, t, J=6.5 Hz), 8.46 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.3 Hz), 8.81-8.98 (3H, m).

Example 48 Synthesis of 1-methyl-3-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 31 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.20-2.42 (2H, m), 3.10-3.33 (2H, m), 3.34-3.60 (4H, m), 3.67 (3H, s), 4.00-4.20 (2H, m), 4.55-4.82 (2H, m), 7.20-7.35 (2H, m), 7.40-7.53 (2H, m), 7.65 (1H, d, J=7.7 Hz), 7.93-8.08 (1H, m), 8.18-8.35 (2H, m), 8.53 (1H, d, J=8.1 Hz), 8.82 (1H, d, J=5.1 Hz), 8.90-9.05 (3H, m).

Example 49 Synthesis of 1-(6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-quinolin-1-yl)ethanone trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 1.71-1.92 (2H, m), 2.11 (3H, s), 2.01-2.39 (2H, m), 2.58-2.79 (2H, m), 3.00-3.48 (6H, m), 3.51-3.71 (2H, m), 3.89-4.10 (2H, m), 4.50 (2H, s), 6.59-6.79 (2H, m), 7.04-7.56 (1H, m), 7.78 (1H, dd, J=7.8, 5.3 Hz), 7.94 (2H, d, J=4.4 Hz), 8.23 (1H, d, J=7.8 Hz), 8.63-8.82 (4H, m).

Example 50 Synthesis of 2,3-dihydrobenzofuran-7-carboxylic acid methyl-(2-{[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)amide dihydrochloride

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC)(144 mg), and 1-hydroxy benzotriazole (HOBt)(115 mg) were added to a DMF solution (5 ml) of 6-{3-[(2-methylaminoethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride (234 mg), and 2,3-dihydrobenzofuran-7-carboxylic acid (123 mg). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water, and dried with anhydrous sodium sulfate. After condensation under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution (0.19 ml) was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (164.6 mg) as a white powder.

¹H-NMR (DMSO-d₆) δppm: 2.04-2.35 (2H, m), 2.65-3.41 (10H, m), 2.90 (3H, s), 3.69-4.66 (8H, m), 6.65-6.90 (3H, m), 6.90-7.14 (1H, m), 7.27 (1H, d, J=5.2 Hz), 7.35-7.61 (1H, m), 7.77 (1H, d, J=8.5 Hz), 7.86-8.19 (2H, m), 8.64-8.90 (2H, m).

Example 51 Synthesis of 1-methyl-6-(3-{[2-(1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 16 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 1.90-2.09 (2H, m), 2.65-2.81 (4H, m), 2.91 (2H, t, J=6.6 Hz), 3.48 (2H, t, J=6.6 Hz), 3.62-3.78 (4H, m), 3.70 (3H, s), 4.01 (2H, t, J=6.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.88 (1H, d, J=2.8 Hz), 7.00-7.48 (7H, m), 7.54 (1H, d, J=9.5 Hz), 8.02-8.11 (1H, m), 8.39-8.50 (2H, m).

Example 52 Synthesis of 2-fluoro-N-methyl-N-(2-{[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]pyridin-4-ylmethylamino}ethyl)benzamide tris(phosphate)

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

Colorless solid (ethanol)

mp: 190-191° C.

Example 53 Synthesis of 1,3-dimethyl-5-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,3-dihydrobenzoimidazol-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.06-2.42 (2H, brs), 2.97-3.73 (m, 12H), 4.04 (2H, t, J=7.0 Hz), 4.42-4.95 (2H, brs), 6.60 (1H, dd, J=2.0, 8.5 Hz), 6.78 (1H, d, J=2.0 Hz), 7.02 (1H, d, J=8.5 Hz), 8.00 (1H, dd, J=5.6, 7.9 Hz), 8.15-8.40 (2H, brs), 8.51 (1H, d, J=7.9 Hz), 8.83 (1H, d, J=5.6 Hz), 8.92 (3H, m), 12.45 (1H, Brs).

Example 54 Synthesis of 1,3-dimethyl-5-{3-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]propoxy}-1,3-dihydrobenzoimidazol-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.17-2.43 (2H, brs), 3.09-3.64 (m, 12H), 3.95-4.18 (2H, m), 4.49-4.84 (2H, brs), 6.63 (1H, dd, J=2.2 and 8.5 Hz), 6.81 (1H, d, J=2.2 Hz), 7.03 (1H, d, J=8.5 Hz), 7.89 (1H, dd, J=7.9 and 5.6 Hz), 8.01 (1H, dd, J=7.9 and 5.6 Hz), 8.26 (1H, d, J=8.0 Hz), 8.71 (1H, d, J=8.0 Hz), 8.77-8.92 (2H, m), 8.96 (1H, s), 9.16 (1H, s), 12.18 (1H, brs).

Example 55 Synthesis of 2-[2-({3-[4-(2-oxopyrrolidin-1-yl)phenoxy]propyl}pyridin-4-ylmeth ylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride

2-(2-{[3-(4-Bromophenoxy)propyl]pyridin-4-ylmethylamino}ethyl)-2H-isoquinolin-1-one (500 mg), 2-pyrrolidone (0.228 ml), potassium carbonate (415 mg), copper iodide (I) (190 mg), and N,N′-dimethyl ethylenediamine (0.39 ml) were added to toluene (5 ml). The mixture was stirred at 100° C. for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. After adding aqueous ammonia, extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, and dried with sodium sulfate. After the organic layer was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→70:30). The purified product was condensed under reduced pressure. A condensed hydrochloric acid (0.3 ml) was added to an ethanol solution of the residue, followed by condensation under reduced pressure. The residue was recrystallized from isopropyl alcohol/water to give the title compound (350 mg) as a white powder.

mp: 210 to 214° C. (dec.)

Example 56 Synthesis of N-methyl-N-[4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}-propoxy)phenyl]acetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.

¹H-NMR (CD₃OD) δppm: 1.82 (3H, s), 2.35-2.54 (2H, m), 3.21 (3H, s), 3.56-3.73 (2H, m), 3.75-3.90 (2H, m), 4.16 (2H, t, J=5.7 Hz), 4.53-4.75 (2H, m), 5.05 (2H, brs), 6.71-6.92 (2H, m), 6.98 (2H, d, J=8.9 Hz), 7.20 (2H, d, J=8.9 Hz), 7.49 (1H, d, J=7.4 Hz), 7.57 (1H, d, J=8.2 Hz), 7.68 (1H, d, J=7.4 Hz), 7.76 (1H, d, J=8.2 Hz), 8.31 (1H, d, J=8.0 Hz), 8.54 (1H, d, J=6.7 Hz), 8.99 (1H, d, J=6.7 Hz).

Example 57 Synthesis of 2-[2-({3-[4-(2-oxopiperidin-1-yl)phenoxy]propyl}-pyridin-4-ylmeth ylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.

¹H-NMR (CD₃OD) δppm: 1.94-2.11 (4H, m), 2.22-2.42 (2H, m), 2.56-2.77 (2H, m), 3.59 (2H, t, J=7.3 Hz), 3.64-3.77 (2H, m), 3.78-3.92 (2H, m), 4.08 (2H, t, J=5.5 Hz), 4.67 (2H, brs), 5.04 (2H, brs), 6.80 (1H, d, J=7.4 Hz), 6.90 (2H, d, J=8.9 Hz), 7.24 (2H, d, J=8.9 Hz), 7.51 (1H, d, J=7.4 Hz), 7.55-7.63 (1H, m), 7.68 (1H, d, J=7.5 Hz), 7.72-7.84 (1H, m), 8.32 (1H, d, J=7.8 Hz), 8.49 (2H, d, J=6.7 Hz), 8.88 (2H, d, J=6.7 Hz).

Example 58 Synthesis of 2-[2-({3-[4-(2-oxo-2H-pyridin-1-yl)phenoxy]propyl}-pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.

¹H-NMR (CD₃OD) δppm: 2.25-2.54 (2H, m), 3.50-3.73 (2H, m), 3.76-3.93 (2H, m), 4.16 (2H, t, J=5.6 Hz), 4.67 (2H, brs), 4.84-5.21 (2H, m), 6.79 (1H, d, J=7.4 Hz), 6.86 (1H, dt, J=1.2 and 6.8 Hz), 6.96 (1H, d, J=8.9 Hz), 7.03 (2H, d, J=8.9 Hz), 7.39 (2H, d, J=8.9 Hz), 7.52 (1H, d, 7.4 Hz), 7.57 (1H, dt, J=1.2 and 8.2 Hz), 7.67 (1H, d, J=7.4 Hz), 7.75 (1H, dt, J=1.2 and 8.2 Hz), 7.82-7.99 (2H, m), 8.32 (1H, d, J=8.1 Hz), 8.53 (1H, d, J=6.6 Hz), 8.94 (1H, d, J=6.6 Hz).

Example 59 Synthesis of 2-[2-({3-[4-(morpholine-4-carbonyl)phenoxy]propyl}-pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride

2-(2-{[3-(4-Bromophenoxy)propyl]pyridin-4-ylmethylamino}ethyl)-2H-isoquinolin-1-one (500 mg), hexacarbonyl molybdenum (264 mg), trans-di-μ-acetatobis[2-(di-o-tolylphosphino)benzyl]dipalladium (II) (Herrmann's palladacycle) (23 mg), sodium carbonate (318 mg), and morpholine (0.26 ml) were added to THF (5 ml). The mixture was heated at 170° C. for 10 minutes (microwave reactor). The reaction mixture was cooled to room temperature. Water and ethyl acetate were added thereto, followed by celite filtration. The organic layer was dried with sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0→7:3). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (150 mg) as a white powder.

¹H-NMR (CD₃OD) δppm: 2.17-2.41 (2H, m), 3.37-3.90 (10H, m), 3.99-4.15 2H, m), 4.50-4.64 (2H, m), 4.67-5.00 (2H, m), 6.81 (1H, d, J=7.4 Hz), 6.88 (2H, d, J=6.2 Hz), 7.38 (2H, d, J=8.5 Hz), 7.45 (1H, d, J=7.4 Hz), 7.60 (1H, t, J=8.2 Hz), 7.71 (1H, d, J=7.4 Hz), 7.79 (1H, t, J=8.2 Hz), 8.32 (1H, d, J=7.9 Hz), 8.38 (2H, brs), 8.83 (2H, brs).

Example 60 Synthesis of 1,3-dimethyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinazoline-2,4-dione trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.11-2.39 (2H, m), 3.00-5.03 (16H, m), 7.25-7.37 (1H, m), 7.37-7.54 (2H, m), 7.94-8.05 (1H, m), 8.05-8.35 (2H, m), 8.49 (1H, d, J=8.2 Hz), 8.73-8.99 (4H, m), 12.24 (1H, brs).

Example 61 Synthesis of 2-[2-(pyridin-4-ylmethyl-{3-[4-(pyrrolidine-1-carbonyl)phenoxy]propyl}amino)ethyl]-2H-isoquinolin-1-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.

¹H-NMR (DMSO-d₆, 80° C.) δppm: 1.75-1.89 (4H, m), 1.92-2.08 (2H, m), 2.78-2.97 (2H, m), 2.99-3.16 (2H, m), 3.35-3.58 (4H, m), 3.91-4.00 (2H, m), 4.07-4.17 (2H, m), 4.17-4.30 (2H, m), 6.57 (1H, d, J=7.3 Hz), 6.79 (2H, d, J=8.8 Hz), 7.41 (2H, d, J=8.8 Hz), 7.34-7.54 (2H, m), 7.56-7.79 (4H, m), 8.20 (1H, d, J=8.7 Hz), 8.53 (2H, d, J=6.2 Hz).

Example 62 Synthesis of N-tert-butyl-4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.

¹H-NMR (DMSO-d₆, 80° C.) δppm: 1.38 (9H, s), 1.92-2.08 (2H, m), 2.83-3.00 (2H, m), 3.04-3.22 (2H, m), 3.96 (2H, d, J=6.2 Hz), 4.10-4.21 (2H, m), 4.21-4.31 (2H, m), 6.59 (1H, d, J=7.3 Hz), 6.77 (2H, d, J=8.8 Hz), 7.23 (1H, brs), 7.42 (1H, d, J=7.3 Hz), 7.49 (1H, m), 7.67 (2H, t, J=7.0 Hz), 7.71 (2H, d, J=8.8 Hz), 7.81 (2H, d, J=6.3), 8.20 (1H, d, J=2.0), 8.56 (2H, d, J=6.3 Hz).

Example 63 Synthesis of N-isobutyl-4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.

¹H-NMR (DMSO-d₆, 80° C.) δppm: 0.90 (6H, d, J=6.5 Hz), 1.75-1.93 (1H, m), 1.93-2.14 (2H, m), 2.85-3.03 (2H, m), 3.03-3.26 (4H, m), 3.90-4.02 (2H, m), 4.15-4.35 (4H, m), 6.59 (1H, d, J=7.4 Hz), 6.80 (2H, d, J=8.8 Hz), 7.31-7.54 (2H, m), 7.61-7.74 (2H, m), 7.76 (2H, d, J=8.8 Hz), 7.86 (2H, d, J=6.3 Hz), 7.98 (1H, brs), 8.20 (1H, d, J=7.4 Hz), 8.59 (2H, d, J=6.3 Hz).

Example 64 Synthesis of N-cyclohexyl-4-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.

¹H-NMR (DMSO-d₆, 80° C.) δppm: 1.00-1.45 (4H, m), 1.53-1.66 (1H, m), 1.66-1.88 (4H, m), 1.92-2.08 (2H, m), 2.82-3.01 (2H, m), 3.04-3.22 (2H, m), 3.65-3.84 (2H, m), 3.88-4.01 (2H, m), 4.21-4.30 (4H, m), 6.58 (1H, d, J=7.3 Hz), 6.79 (2H, d, J=8.8 Hz), 7.42 (1H, d, J=7.3 Hz), 7.46-7.53 (1H, m), 7.57-7.84 (7H, m), 8.20 (1H, d, J=7.3 Hz), 8.56 (2H, d, J=6.4 Hz).

Example 65 1-methyl-6-(3-{[2-(1-oxo-2H-isoquinolin-2-yl)ethyl]pyridin-4-ylmethylamino}propoxy)-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

Colorless solid (isopropyl alcohol/water)

mp: 171 to 174° C.

Example 66 Synthesis of 2-[2-({3-[4-(2-oxo-oxazolidin-3-yl)phenoxy]propyl}pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.

¹H-NMR (DMSO-d₆, 80° C.) δppm: 1.87-2.08 (2H, m), 2.79-3.00 (2H, m), 3.01-3.21 (2H, m), 3.86-3.96 (2H, m), 3.96-4.05 (2H, m), 4.11-4.33 (4H, m), 4.34-4.49 (2H, m), 6.58 (1H, d, J=7.4 Hz), 6.79 (2H, d, J=9.1 Hz), 7.39 (2H, d, J=9.1 Hz), 7.33-7.44 (1H, m), 7.44-7.55 (2H, m), 7.57-7.73 (2H, m), 7.77-7.87 (2H, m), 8.20 (1H, d, J=8.0 Hz), 8.50-8.64 (2H, m).

Example 67 Synthesis of 2-[2-({3-[3-(2-oxopyrrolidin-1-yl)phenoxy]propyl}pyridin-4-ylmethylamino)ethyl]-2H-isoquinolin-1-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 55 using appropriate starting materials.

¹H-NMR (DMSO-d₆, 80° C.) δppm: 1.85-2.16 (4H, m), 2.35-2.55 (2H, m), 2.79-3.01 (2H, m), 3.01-3.21 (2H, m), 3.73-4.26 (8H, m), 6.49-6.63 (2H, m), 7.04-7.14 (1H, m), 7.14-7.28 (2H, m), 7.35-7.54 (2H, m), 7.55-7.72 (2H, m), 7.72-7.92 (2H, m), 8.19 (1H, dd, J=8.1 and 0.6 Hz), 8.47-8.66 (2H, m).

Example 68 Synthesis of 2-[2-(pyridin-4-ylmethyl-{3-[3-(pyrrolidine-1-carbonyl)phenoxy]propyl}amino)ethyl]-2H-isoquinolin-1-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 59 using appropriate starting materials.

¹H-NMR (DMSO-d₆, 80° C.) δppm: 1.72-1.90 (4H, m), 1.94-2.14 (2H, m), 2.86-3.05 (2H, m), 3.05-3.22 (2H, m), 3.25-3.50 (4H, m), 3.70-4.36 (6H, m), 6.58 (1H, d, J=7.4 Hz), 6.78-6.95 (2H, m), 7.01 (1H, d, J=7.7 Hz), 7.28 (1H, t, J=7.9 Hz), 7.42 (1H, d, J=7.4 Hz), 7.44-7.51 (1H, m), 7.55-7.74 (2H, m), 7.83 (2H, d, J=4.9 Hz), 8.20 (1H, d, J=8.1 Hz), 8.58 (2H, d, J=5.6 Hz).

Example 69 Synthesis of 5-{2-[[3-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yloxy) propyl]-(2-methylpyridin-3-ylmethyl)amino]ethyl}-2-methyl-5H-furo[3,2-c]pyridin-4-one

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 1.92-1.95 (2H, m), 2.40 (3H, s), 2.48 (3H, s), 2.76 (2H, t, J=6.9 Hz), 2.86 (2H, t, J=6.2 Hz), 3.39 (3H, s), 3.40 (3H, s), 3.63 (2H, s), 3.90 (2H, t, J=6.0 Hz), 4.01 (2H, t, J=6.2 Hz), 6.31 (1H, dd, J=7.3, 0.6 Hz), 6.49-6.51 (2H, m), 6.54 (1H, dd, J=8.5, 2.3 Hz), 6.83 (1H, d, J=8.4 Hz), 6.86 (1H, dd, J=7.7, 4.9 Hz), 6.93 (1H, d, J=7.3 Hz), 7.42-7.44 (1H, m), 8.28-8.30 (1H, m).

Example 70 Synthesis of 2-{2-[[3-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yloxy) propyl]-(2-methylpyridin-3-ylmethyl)amino]ethyl}-2H-isoquinolin-1-one

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 1.92-1.96 (2H, m), 2.48 (3H, s), 2.76 (2H, t, J=6.9 Hz), 2.88 (2H, t, J=6.2 Hz), 3.38 (3H, s), 3.39 (3H, s), 3.63 (2H, s), 3.91 (2H, t, J=6.0 Hz), 4.01 (2H, t, J=6.2 Hz), 6.35 (1H, d, J=7.3 Hz), 6.47 (1H, d, J=2.3 Hz), 6.50 (1H, dd, J=8.4, 2.3 Hz), 6.72 (1H, dd, J=7.6, 4.8 Hz), 6.81 (1H, d, J=8.4 Hz), 6.90 (1H, d, J=7.3 Hz), 7.41 (1H, dd, J=7.6, 1.5 Hz), 7.44-7.49 (2H, m), 7.60-7.65 (1H, m), 8.20-8.22 (1H, m), 8.34-8.36 (1H, m).

Example 71 Synthesis of 1-methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]ethoxy}-1H-quinolin-2-one trihydrochloride

A 1N-hydrogen chloride ethanol solution (1.7 ml) was added to an ethanol solution (10 ml) of 1-Methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-3-ylmethylamino]ethoxy}-1H-quinolin-2-one (195 mg), which was stirred at room temperature. The reaction mixture was condensed under reduced pressure and ethyl acetate was added to the residue. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (199 mg) as a pale yellow powder.

¹H-NMR (DMSO-d₆), δppm: 3.08-5.02 (10H, m), 3.61 (3H, s), 6.64 (1H, d, J=9.5 Hz), 7.26-7.38 (2H, m), 7.49 (1H, d, J=9.3 Hz), 7.75-7.83 (1H, m), 7.86 (1H, d, J=9.5 Hz), 7.92 (1H, dd, J=8.0, 5.6 Hz), 8.41 (1H, d, J=8.0 Hz), 8.42-8.53 (1H, m), 8.73-8.81 (2H, m), 8.87 (1H, s), 8.92-9.05 (1H, m).

Example 72 Synthesis of 1-methyl-6-{2-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]ethoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 3.02-5.62 (10H, m), 3.61 (3H, s), 6.63 (1H, d, J=9.5 Hz), 7.21-7.34 (2H, m), 7.47 (1H, d, J=9.1 Hz), 7.85 (1H, d, J=9.5 Hz), 7.92-8.01 (1H, m), 8.02-8.21 (2H, m), 8.49 (1H, d, J=8.0 Hz), 8.77 (1H, d, J=5.3 Hz), 8.82-8.92 (3H, m).

Example 73 Synthesis of 1-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.18-2.43 (2H, m), 3.07-3.49 (4H, m), 3.60 (3H, s), 4.05-4.18 (2H, m), 4.50-4.88 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.7 Hz), 7.27 (1H, d, J=2.7 Hz), 7.47 (1H, d, J=9.1 Hz), 7.84 (1H, d, J=9.5 Hz), 7.94-8.05 (1H, m), 8.08-8.36 (2H, m), 8.49 (1H, d, J=7.6 Hz), 8.82 (1H, d, J=4.9 Hz), 8.83-8.99 (3H, m).

Example 74 Synthesis of 1-methyl-6-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.14-2.38 (2H, m), 2.77-4.95 (14H, m), 3.22 (3H, s), 6.73-6.82 (2H, m), 6.99 (1H, d, J=9.2 Hz), 7.99 (1H, d, J=5.7 Hz), 8.22-8.34 (2H, m), 8.52 (1H, d, J=8.1 Hz), 8.81-8.98 (4H, m).

Example 75 Synthesis of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(quinolin-6-yloxy)propyl]amine tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 71 using appropriate starting materials.

¹H-NMR (DMSO-d₆) δppm: 2.22-4.78 (12H, m), 7.51-7.61 (2H, m), 7.73-7.97 (4H, m), 8.15 (1H, d, J=9.1 Hz), 8.20-8.33 (1H, m), 8.62-8.81 (5H, m), 8.98 (1H, d, J=4.9 Hz).

Example 76 Synthesis of 6-{5-[benzo[1,3]dioxol-5-ylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.31-1.50 (2H, m), 1.68-1.93 (4H, m), 2.95-3.12 (2H, m), 3.12-3.40 (4H, m), 3.58 (3H, s), 3.91-4.38 (4H, m), 6.05 (2H, s), 6.59 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=8.0 Hz), 7.10 (1H, dd, J=8.0, 1.5 Hz), 7.23 (1H, dd, J=9.1, 2.9 Hz), 7.27 (1H, d, J=2.9 Hz), 7.30 (1H, d, J=1.5 Hz), 7.44 (1H, d, J=9.1 Hz), 7.78-7.87 (2H, m), 8.26 (1H, d, J=8.0 Hz), 8.73 (1H, d, J=5.4 Hz), 8.79 (1H, s).

Example 77 Synthesis of 6-{5-[benzofuran-2-ylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.40-1.59 (2H, m), 1.68-1.83 (2H, m), 1.83-2.00 (2H, m), 3.04-3.24 (2H, m), 3.24-3.50 (4H, m), 3.58 (3H, s), 3.92-4.11 (2H, m), 4.70 (2H, s), 6.59 (1H, d, J=9.5 Hz), 7.19-7.41 (5H, m), 7.44 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=7.3 Hz), 7.82 (1H, d, J=9.5 Hz), 7.96 (1H, dd, J=8.0, 5.2 Hz), 8.46 (1H, d, J=8.0 Hz), 8.79 (1H, d, J=5.2 Hz), 8.90 (1H, s).

Example 78 Synthesis of 6-{5-[benzo[b]thiophen-3-ylmethyl-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.30-1.49 (2H, m), 1.60-1.98 (4H, m), 3.08-3.28 (2H, m), 3.28-3.51 (4H, m), 3.58 (3H, s), 3.90-4.08 (2H, m), 4.72 (2H, s), 6.59 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.39-7.52 (3H, m), 7.82 (1H, d, J=9.5 Hz), 7.90 (1H, dd, J=7.9, 5.4 Hz), 8.06 (1H, d, J=8.7 Hz), 8.14 (1H, d, J=7.3 Hz), 8.30-8.40 (2H, m), 8.76 (1H, d, J=5.4 Hz), 8.85 (1H, s).

Example 79 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(pyridin-2-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.39-1.55 (2H, m), 1.69-1.82 (2H, m), 1.69-2.01 (2H, m), 3.11-3.31 (2H, m), 3.39-3.57 (4H, m), 3.60 (3H, s), 3.96-4.11 (2H, m), 4.67 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.2, 2.8 Hz), 7.31 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.59 (1H, dd, J=6.8, 5.4 Hz), 7.86 (1H, d, J=9.5 Hz), 7.94 (1H, d, J=7.8 Hz), 8.02-8.12 (2H, m), 8.60 (1H, d, J=8.1 Hz), 8.73 (1H, d, J=4.7 Hz), 8.87 (1H, d, J=5.4 Hz), 8.87 (1H, s).

Example 80 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(pyridin-3-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.40-1.58 (2H, m), 1.71-1.88 (2H, m), 1.88-2.09 (2H, m), 3.08-3.32 (2H, m), 3.32-3.56 (4H, m), 3.60 (3H, s), 3.96-4.10 (2H, m), 4.79 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.2, 2.8 Hz), 7.33 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.87 (1H, d, J=9.5 Hz), 8.08 (1H, dd, J=8.1, 5.7 Hz), 8.16 (1H, dd, J=8.1, 5.8 Hz), 8.65 (1H, d, J=8.1 Hz), 8.87 (1H, d, J=5.7 Hz), 9.02 (1H, d, J=5.8 Hz), 9.04 (1H, s), 9.08 (1H, d, J=8.1 Hz), 9.39 (1H, s).

Example 81 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

Triethylamine (0.35 ml) was added to a dichloromethane solution (5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (219 mg) and ice-cooled. Benzenesulfonyl chloride (0.096 ml) was added to the resulting mixture, and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.16 ml) was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (68 mg) as a yellow powder.

1H-NMR (DMSO-D6) δppm: 1.19-1.39 (2H, m), 1.39-1.55 (2H, m), 1.55-1.78 (2H, m), 2.92-3.20 (4H, m), 3.31-3.50 (2H, m), 3.58 (3H, s), 3.86-4.07 (2H, m), 6.59 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.51-7.71 (3H, m), 7.71-7.89 (3H, m), 7.99 (1H, dd, J=8.0, 5.7 Hz), 8.49 (1H, d, J=8.0 Hz), 8.79 (1H, d, J=5.7 Hz), 8.87 (1H, s).

Example 82 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 2.00-2.19 (2H, m), 2.92 (2H, t, J=7.6 Hz), 3.50-3.66 (4H, m), 3.71 (3H, s), 4.01 (2H, t, J=5.8 Hz), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.13 (1H, dd, J=9.2, 2.8 Hz), 7.19 (1H, dd, J=7.8, 5.4 Hz), 7.29 (1H, d, J=9.2 Hz), 7.50-7.64 (5H, m), 7.96-8.02 (1H, m), 8.42 (1H, d, J=1.7 Hz), 8.46 (1H, dd, J=4.8, 1.7 Hz).

Example 83 Synthesis of N-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)butyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.70-1.89 (4H, m), 2.89 (2H, t, J=7.5 Hz), 3.40-3.60 (4H, m), 3.68 (3H, s), 4.01 (2H, t, J=5.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.13-7.22 (2H, m), 7.29 (1H, d, J=9.2 Hz), 7.49-7.72 (5H, m), 7.95-8.01 (1H, m), 8.40 (1H, d, J=1.7 Hz), 8.44 (1H, dd, J=4.9, 1.7 Hz).

Example 84 Synthesis of 1-methyl-6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.45 (2H, m), 2.48 (3H, s), 3.60 (3H, s), 3.10-4.65 (10H, m), 6.63 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.41 (4H, m), 7.48 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=7.0 Hz), 7.84 (1H, d, J=9.5 Hz), 7.96 (1H, dd, J=7.8, 5.5 Hz), 8.43 (1H, d, J=7.8 Hz), 8.80 (1H, d, J=5.5 Hz), 8.90 (1H, s).

Example 85 Synthesis of 1-methyl-6-{4-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.61-1.86 (2H, m), 1.86-2.14 (2H, m), 2.48 (3H, s), 3.10-3.33 (2H, m), 3.33-3.58 (4H, m), 3.60 (3H, s), 3.90-4.80 (4H, m), 6.61 (1H, d, J=9.5 Hz), 7.18-7.37 (5H, m), 7.47 (1H, d, J=9.2 Hz), 7.75 (1H, d, J=7.4 Hz), 7.85 (1H, d, J=9.5 Hz), 8.05 (1H, dd, J=8.0, 5.5 Hz), 8.56 (1H, d, J=8.0 Hz), 8.85 (1H, d, J=5.5 Hz), 8.98 (1H, s).

Example 86 Synthesis of 1-methyl-6-{3-[N-(3-phenylpropyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.91-2.12 (2H, m), 2.12-2.31 (2H, m), 2.59-2.78 (2H, m), 3.58 (3H, s), 3.05-4.39 (10H, m), 6.60 (1H, d, J=9.5 Hz), 7.13-7.34 (7H, m), 7.45 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 7.98 (1H, dd, J=7.9, 5.5 Hz), 8.51 (1H, d, J=7.9 Hz), 8.80 (1H, d, J=5.5 Hz), 8.92 (1H, s).

Example 87 Synthesis of 1-methyl-6-{4-[N-(3-phenylpropyl)-N-(2-pyridin-3-ylethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.71-2.15 (6H, m), 2.55-2.75 (2H, m), 3.57 (3H, s), 3.00-4.34 (10H, m), 6.59 (1H, d, J=9.5 Hz), 7.14-7.32 (7H, m), 7.44 (1H, d, J=9.2 Hz), 7.81 (1H, d, J=9.5 Hz), 7.99 (1H, dd, J=7.9, 5.5 Hz), 8.53 (1H, d, J=7.9 Hz), 8.81 (1H, d, J=5.5 Hz), 8.93 (1H, s).

Example 88 Synthesis of 1-methyl-6-{5-[N-((E)-3-phenylallyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.40-1.60 (2H, m), 1.71-2.00 (4H, m), 3.59 (3H, s), 2.97-4.20 (10H, m), 6.51 (1H, dt, J=15.9, 7.0 Hz), 6.61 (1H, d, J=9.5 Hz), 6.95 (1H, d, J=15.9 Hz), 7.20-7.54 (8H, m), 7.83 (1H, d, J=9.5 Hz), 8.00 (1H, dd, J=8.0, 5.5 Hz), 8.53 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.5 Hz), 8.96 (1H, s).

Example 89 Synthesis of N-methyl-4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzamide dihydrochloride

Diethyl phosphorocyanidate (39.1 mg) was added to a DMF solution (1 ml) of 4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid (0.10 g), methylamine hydrochloride (27 mg), and triethylamine (0.07 ml), and the mixture was stirred at room temperature overnight. Ice water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution (0.16 ml) was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (81.3 mg) as a white powder.

1H-NMR (CDCl3) δppm: 1.40-1.89 (6H, m), 2.54 (2H, t, J=6.2 Hz), 2.71-2.76 (4H, m), 3.03 (3H, d, J=4.9 Hz), 3.66 (2H, s), 3.73 (3H, s), 3.98 (2H, t, J=6.4 Hz), 6.22-6.31 (1H, m), 6.74 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.16-7.20 (2H, m), 7.28-7.33 (3H, m), 7.42-7.68 (4H, m), 8.41-7.46 (2H, m).

Example 90 Synthesis of N-ethyl-4-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 89 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.11 (3H, t, J=7.2 Hz), 1.34-1.50 (2H, m), 1.70-1.96 (4H, m), 3.60 (3H, s), 3.00-4.60 (12H, m), 6.62 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.78 (2H, d, J=8.2 Hz), 7.85 (1H, d, J=9.5 Hz), 7.86-7.96 (3H, m), 8.31 (1H, d, J=8.0 Hz), 8.55-8.64 (1H, m), 8.76 (1H, d, J=5.2 Hz), 8.80-8.85 (1H, m).

Example 91 Synthesis of N,N-dimethyl-4-{[[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl](2-pyridin-3-ylethyl)amino]methyl}benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 89 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.35-1.51 (2H, m), 1.68-1.92 (4H, m), 2.89 (3H, s), 3.00 (3H, s), 3.60 (3H, s), 3.04-4.59 (10H, m), 6.62 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.43-7.52 (3H, m), 7.75 (2H, d, J=8.1 Hz), 7.85 (1H, d, J=9.5 Hz), 7.81-7.89 (1H, m), 8.29 (1H, d, J=8.0 Hz), 8.75 (1H, d, J=5.4 Hz), 8.81 (1H, s).

Example 92 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(quinolin-2-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.41-1.60 (2H, m), 1.69-1.88 (2H, m), 1.88-2.06 (2H, m), 3.60 (3H, s), 3.21-4.26 (8H, m), 4.85 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.45 (1H, d, J=9.2 Hz), 7.65-7.74 (1H, m), 7.79-7.91 (3H, m), 8.02-8.13 (3H, m), 8.53 (1H, d, J=8.5 Hz), 8.59 (1H, d, J=8.2 Hz), 8.86 (1H, d, J=5.4 Hz), 9.00 (1H, s).

Example 93 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(quinolin-3-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.42-1.60 (2H, m), 1.72-1.90 (2H, m), 1.90-2.10 (2H, m), 3.60 (3H, s), 3.14-4.36 (8H, m), 4.76 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.79-7.90 (2H, m), 7.97-8.08 (2H, m), 8.17 (1H, d, J=7.9 Hz), 8.27 (1H, d, J=8.6 Hz), 8.57 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=5.3 Hz), 8.99 (1H, s), 9.13 (1H, s), 9.45 (1H, d, J=1.7 Hz).

Example 94 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.33-1.52 (2H, m), 1.63-1.82 (2H, m), 1.82-2.04 (2H, m), 3.60 (3H, s), 2.99-4.26 (8H, m), 5.00-5.30 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.7 Hz), 7.28 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.87-7.96 (1H, m), 7.96-8.12 (2H, m), 8.37 (1H, d, J=8.5 Hz), 8.42-8.66 (3H, m), 8.83 (1H, d, J=5.5 Hz), 8.94 (1H, s), 9.25 (1H, d, J=5.1 Hz).

Example 95 Synthesis of 1-methyl-6-{5-[N-(naphthalen-2-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.31-1.56 (2H, m), 1.67-1.82 (2H, m), 1.82-2.05 (2H, m), 3.05-3.25 (2H, m), 3.60 (3H, s), 3.36-4.20 (6H, m), 4.49-4.75 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.7 Hz), 7.28 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.2 Hz), 7.53-7.65 (2H, m), 7.81-8.08 (6H, m), 8.24 (1H, s), 8.55 (1H, d, J=8.2 Hz), 8.83 (1H, d, J=5.4 Hz), 8.98 (1H, s).

Example 96 Synthesis of 1-methyl-6-{5-[N-(pyridin-2-yl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride

1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one (182 mg), 2-bromopyridine (0.060 ml), palladium acetate (II) (11.2 mg), xantphos (32 mg), and sodium t-butoxide (68 mg) were added to toluene (2 ml). The mixture was heated at 80° C. for 10 hours under nitrogen atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (0.58 ml) was added to a ethanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and diethyl ether were added to the residue. The precipitated insoluble matter was separated, washed with diethyl ether, and dried to give the title compound (72 mg) as a yellow powder.

1H-NMR (DMSO-D6) δppm: 1.42-1.91 (6H, m), 3.60 (3H, s), 3.09-4.36 (8H, m), 6.62 (1H, d, J=9.5 Hz), 6.98 (1H, t, J=6.6 Hz), 7.24 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.38 (1H, d, J=9.1 Hz), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 7.98-8.11 (3H, m), 8.76-8.88 (2H, m), 9.16 (1H, s).

Example 97 Synthesis of N-[4-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)butyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.50-1.76 (4H, m), 3.00-3.15 (2H, m), 3.15-3.29 (2H, m), 3.40-3.55 (2H, m), 3.60 (3H, s), 3.91-4.01 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.54-7.73 (3H, m), 7.77-7.89 (3H, m), 8.02 (1H, dd, J=8.0, 5.6 Hz), 8.52 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.6 Hz), 8.90 (1H, s).

Example 98 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)phenylmethanesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.21-1.41 (2H, m), 1.41-1.59 (2H, m), 1.59-1.79 (2H, m), 2.91-3.18 (4H, m), 3.30-3.48 (2H, m), 3.59 (3H, s), 3.90-4.08 (2H, m), 4.44 (2H, s), 6.60 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.32-7.43 (5H, m), 7.45 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=8.0, 5.5 Hz), 8.47 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.5 Hz), 8.87 (1H, s).

Example 99 Synthesis of 2,4,6-trimethyl-N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.21-1.41 (2H, m), 1.41-1.75 (4H, m), 2.22 (3H, s), 2.37 (6H, s), 2.93-3.08 (2H, m), 3.26-3.38 (2H, m), 3.45-3.59 (2H, m), 3.60 (3H, s), 3.89-4.02 (2H, m), 6.61 (1H, d, J=9.5 Hz), 6.87 (2H, s), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.79-7.88 (2H, m), 8.32 (1H, d, J=8.0 Hz), 8.71-8.79 (2H, m).

Example 100 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)biphenyl-4-sulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.25-1.45 (2H, m), 1.45-1.63 (2H, m), 1.62-1.81 (2H, m), 3.00-3.18 (2H, m), 3.18-3.30 (2H, m), 3.41-3.57 (2H, m), 3.58 (3H, s), 3.90-4.10 (2H, m), 6.60 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.41-7.51 (4H, m), 7.69-7.72 (2H, m), 7.81 (1H, d, J=9.5 Hz), 7.85-7.90 (4H, m), 8.00-8.05 (1H, m), 8.53 (1H, d, J=5.5 Hz), 8.82 (1H, d, J=5.5 Hz), 8.92 (1H, s).

Example 101 Synthesis of 6-[3-[N,N-bis(pyridin-3-ylmethyl)amino]propoxy]-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.05-2.36 (2H, m), 2.84-3.19 (2H, m), 3.60 (3H, s), 3.94-4.12 (2H, m), 4.40-4.71 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.6 Hz), 7.24 (1H, d, J=2.6 Hz), 7.45 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.00 (2H, dd, J=7.7, 5.4 Hz), 8.77 (2H, d, J=7.7 Hz), 8.90 (2H, dd, J=5.4 Hz), 9.14 (2H, s).

Example 102 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.21-1.44 (2H, m), 1.51-1.75 (4H, m), 2.98-3.19 (2H, m), 3.19-3.40 (2H, m), 3.59 (3H, s), 3.59-3.78 (2H, m), 3.89-4.08 (2H, m), 6.58 (1H, d, J=9.5 Hz), 7.14-7.28 (4H, m), 7.33-7.47 (4H, m), 7.79 (1H, d, J=9.5 Hz), 7.87-7.99 (1H, m), 8.25-8.45 (1H, m), 8.74 (1H, d, J=5.4 Hz), 8.69-8.85 (1H, m).

Example 103 Synthesis of 2-methyl-N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.21-1.49 (2H, m), 1.49-1.80 (4H, m), 2.13 (3H, s), 2.89-3.77 (6H, m), 3.58 (3H, s), 3.86-4.10 (2H, m), 6.55 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=7.4 Hz), 7.10-7.28 (5H, m), 7.35-7.43 (1H, m), 7.59-7.73 (1H, m), 7.74 (1H, d, J=9.5 Hz), 7.89-8.23 (1H, m), 8.46-8.69 (1H, m), 8.59 (1H, d, J=5.9 Hz).

Example 104 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)-nicotinamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.28-1.48 (2H, m), 1.52-1.79 (4H, m), 2.78-3.00 (2H, m), 3.22-3.51 (2H, m), 3.58 (3H, s), 3.51-3.67 (2H, m), 3.91-4.06 (2H, m), 6.55 (1H, d, J=9.5 Hz), 7.15-7.28 (3H, m), 7.33-7.42 (2H, m), 7.47-7.55 (1H, m), 7.55-7.63 (1H, m), 7.74 (1H, d, J=9.5 Hz), 8.32-8.44 (3H, m), 8.57 (1H, dd, J=4.8, 1.7 Hz).

Example 105 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(thiophen-2-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.38-1.56 (2H, m), 1.68-2.00 (4H, m), 3.00-3.19 (2H, m), 3.27-3.49 (4H, m), 3.60 (3H, s), 3.92-4.10 (2H, m), 4.67 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.14 (1H, dd, J=5.1, 3.5 Hz), 7.25 (1H, dd, J=9.1, 2.8 Hz), 7.31 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.49-7.54 (1H, m), 7.72 (1H, dd, J=5.1, 1.1 Hz), 7.85 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.0, 5.6 Hz), 8.50 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.93 (1H, s).

Example 106 Synthesis of 1-methyl-6-{5-[N-(2-pyridin-3-ylethyl)-N-(thiophen-3-ylmethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.35-1.55 (2H, m), 1.69-2.00 (4H, m), 2.95-3.14 (2H, m), 3.29-3.51 (4H, m), 3.60 (3H, s), 3.97-4.10 (2H, m), 4.43 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.25 (1H, dd, J=9.1, 2.7 Hz), 7.31 (1H, d, J=2.7 Hz), 7.44-7.52 (2H, m), 7.63-7.69 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.95 (1H, d, J=1.8 Hz), 8.05 (1H, dd, J=8.1, 5.6 Hz), 8.54 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.6 Hz), 8.96 (1H, s).

Example 107 Synthesis of 1-methyl-6-{5-[N-(pyridin-3-yl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 96 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.40-1.55 (4H, m), 1.66-1.87 (2H, m), 2.98-3.15 (2H, m), 3.32-4.10 (6H, m), 3.59 (3H, s), 6.61 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.1, 2.9 Hz), 7.28 (1H, d, J=2.9 Hz), 7.45 (1H, d, J=9.1 Hz), 7.77 (1H, dd, J=9.0, 5.0 Hz), 7.83 (1H, d, J=9.5 Hz), 7.88-8.09 (3H, m), 8.35 (1H, d, J=2.6 Hz), 8.61 (1H, d, J=8.1 Hz), 8.81 (1H, d, J=5.5 Hz), 9.01 (1H, s).

Example 108 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.95-2.10 (2H, m), 3.50 (2H, t, J=7.2 Hz), 3.58 (3H, s), 3.75-4.18 (2H, m), 4.77 (2H, s), 6.57 (1H, d, J=9.5 Hz), 7.08 (1H, dd, J=9.1, 2.7 Hz), 7.12 (1H, d, J=2.7 Hz), 7.35-7.45 (6H, m), 7.70-7.79 (1H, m), 7.75 (1H, d, J=9.5 Hz), 8.18 (1H, d, J=6.9 Hz), 8.67 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 109 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.82-2.00 (2H, m), 3.02-3.15 (2H, m), 3.29-3.39 (2H, m), 3.45-3.54 (2H, m), 3.60 (3H, s), 3.97 (2H, t, J=6.0 Hz), 6.62 (1H, d, J=9.5 Hz), 7.19-7.27 (2H, m), 7.47 (1H, d, J=9.1 Hz), 7.53-7.71 (3H, m), 7.77-7.83 (2H, m), 7.85 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.0, 5.5 Hz), 8.53 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.5 Hz), 8.91 (1H, s).

Example 110 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.45 (2H, m), 3.18-3.35 (2H, m), 3.35-3.53 (4H, m), 3.60 (3H, s), 4.01-4.20 (2H, m), 4.50-4.78 (2H, m), 6.63 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.1, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=9.1 Hz), 7.82-7.93 (1H, m), 7.85 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=8.2, 5.8 Hz), 8.52 (1H, d, J=8.2 Hz), 8.67 (1H, d, J=7.0 Hz), 8.80-8.90 (2H, m), 8.95 (1H, s), 9.14 (1H, s).

Example 111 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)ethanesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.15 (3H, t, J=7.4 Hz), 1.30-1.49 (2H, m), 1.49-1.65 (2H, m), 1.65-1.82 (2H, m), 2.80-2.93 (2H, m), 3.14-3.50 (6H, m), 3.59 (3H, s), 4.02 (2H, t, J=6.4 Hz), 6.60 (1H, d, J=9.5 Hz), 7.23 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.45 (1H, d, J=9.2 Hz), 7.39-7.48 (1H, m), 7.83 (1H, d, J=9.5 Hz), 7.78-7.85 (1H, m), 8.48 (1H, d, J=5.2 Hz), 8.54 (1H, s).

Example 112 Synthesis of N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)cyclohexylmethanesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 0.90-1.89 (17H, m), 2.75-2.95 (4H, m), 3.08-3.49 (4H, m), 3.59 (3H, s), 4.02 (2H, t, J=6.5 Hz), 6.60 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.0, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.42 (1H, dd, J=7.9, 4.9 Hz), 7.45 (1H, d, J=9.0 Hz), 7.77-7.82 (1H, m), 7.83 (1H, d, J=9.5 Hz), 8.48 (1H, dd, J=4.9, 1.6 Hz), 8.53 (1H, d, J=1.6 Hz).

Example 113 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.70-1.91 (2H, m), 3.36 (2H, t, J=7.7 Hz), 3.60 (3H, s), 3.89 (2H, t, J=6.0 Hz), 4.60 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.11-7.19 (2H, m), 7.44 (1H, d, J=8.8 Hz), 7.60-7.77 (3H, m), 7.83 (1H, d, J=9.5 Hz), 7.92 (2H, d, J=7.2 Hz), 8.03 (1H, dd, J=8.0, 5.6 Hz), 8.55 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.89 (1H, s).

Example 114 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 3.10-3.25 (2H, m), 3.60 (3H, s), 3.70-3.90 (4H, m), 4.11-4.28 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.10 (1H, dd, J=9.2, 2.9 Hz), 7.23 (1H, d, J=2.9 Hz), 7.44 (1H, d, J=9.2 Hz), 7.74-7.91 (3H, m), 7.93-8.09 (3H, m), 8.53 (1H, d, J=8.1 Hz), 8.79 (1H, d, J=5.5 Hz), 8.93 (1H, s).

Example 115 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)phenylmethanesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.88-2.04 (2H, m), 3.00-3.14 (2H, m), 3.23-3.39 (2H, m), 3.39-3.51 (2H, m), 3.60 (3H, s), 3.89-4.09 (2H, m), 4.47 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21-7.30 (2H, m), 7.33-7.44 (5H, m), 7.48 (1H, d, J=9.0 Hz), 7.86 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.0, 5.5 Hz), 8.47 (1H, d, J=8.0 Hz), 8.81 (1H, d, J=5.5 Hz), 8.87 (1H, s).

Example 116 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)phenylmethanesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.71-1.89 (2H, m), 3.24-3.41 (2H, m), 3.59 (3H, s), 3.88 (2H, t, J=6.0 Hz), 4.55 (2H, s), 4.67 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.09-7.21 (2H, m), 7.34-7.51 (6H, m), 7.83 (1H, d, J=9.5 Hz), 7.94-8.06 (1H, m), 8.50 (1H, d, J=7.9 Hz), 8.81 (1H, d, J=5.1 Hz), 8.85 (1H, s).

Example 117 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-N-(2-pyridin-3-ylethyl)phenylmethanesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 3.01-3.19 (2H, m), 3.40-3.61 (4H, m), 3.60 (3H, s), 4.00-4.15 (2H, m), 4.54 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.0, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.32-7.44 (5H, m), 7.48 (1H, d, J=9.0 Hz), 7.86 (1H, d, J=9.5 Hz), 8.02 (1H, dd, J=8.1, 5.6 Hz), 8.49 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=5.6 Hz), 8.87 (1H, s).

Example 118 Synthesis of 1-methyl-6-{2-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]ethoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.48 (3H, s), 3.35-3.84 (6H, m), 3.61 (3H, s), 4.59 (4H, s), 6.64 (1H, d, J=9.5 Hz), 7.23-7.41 (5H, m), 7.50 (1H, d, J=9.2 Hz), 7.80 (1H, d, J=7.4 Hz), 7.86 (1H, d, J=9.5 Hz), 8.03 (1H, dd, J=8.0, 5.5 Hz), 8.53 (1H, d, J=8.0 Hz), 8.85 (1H, d, J=5.5 Hz), 8.96 (1H, s).

Example 119 Synthesis of 2-methyl-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.80-2.06 (2H, m), 2.17 (3H, s), 3.26-3.49 (2H, m), 3.59 (3H, s), 3.78-4.00 (2H, m), 4.80-5.01 (2H, m), 6.58 (1H, d, J=9.5 Hz), 6.91-7.51 (7H, m), 7.77 (1H, d, J=9.5 Hz), 7.89-8.11 (1H, m), 8.44-8.65 (1H, m), 8.73-8.90 (1H, m), 8.90-9.03 (1H, m).

Example 120 Synthesis of 6-[2-[N,N-bis-(pyridin-3-ylmethyl)amino]ethoxy]-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.85-3.15 (2H, m), 3.61 (3H, s), 3.89-4.41 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.25-7.34 (2H, m), 7.46 (1H, d, J=8.8 Hz), 7.83 (1H, d, J=9.5 Hz), 7.89-8.01 (2H, m), 8.50-8.60 (2H, m), 8.80 (2H, d, J=5.2 Hz), 8.95 (2H, s).

Example 121 Synthesis of 6-[2-[N,N-bis-(pyridin-4-ylmethyl)amino]ethoxy]-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.91-3.05 (2H, m), 3.60 (3H, s), 4.14 (4H, s), 4.12-4.29 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.21-7.27 (2H, m), 7.41-7.48 (1H, m), 7.80 (1H, d, J=9.5 Hz), 8.09 (4H, d, J=6.5 Hz), 8.84 (4H, d, J=6.5 Hz).

Example 122 Synthesis of 6-[3-[N,N-bis-(pyridin-4-ylmethyl)amino]propoxy]-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.96-2.19 (2H, m), 2.70-2.98 (2H, m), 3.60 (3H, s), 3.92-4.10 (2H, m), 4.10-4.43 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.08 (1H, dd, J=9.2, 2.8 Hz), 7.23 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=9.5 Hz), 8.23 (4H, d, J=6.0 Hz), 8.88 (4H, d, J=6.0 Hz).

Example 123 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 3.07-3.21 (2H, m), 3.49-3.69 (4H, m), 3.60 (3H, s), 4.05-4.23 (2H, m), 6.63 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.1, 2.9 Hz), 7.25 (1H, d, J=2.9 Hz), 7.46 (1H, d, J=9.1 Hz), 7.53-7.72 (3H, m), 7.79-7.89 (3H, m), 8.01 (1H, dd, J=8.1, 5.6 Hz), 8.53 (1H, d, J=8.1 Hz), 8.79 (1H, d, J=5.6 Hz), 8.89 (1H, s).

Example 124 Synthesis of 2-methyl-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.82-2.00 (2H, m), 2.12 (3H, s), 2.88-3.50 (6H, m), 3.59 (3H, s), 4.04-4.30 (2H, m), 6.59 (1H, d, J=9.5 Hz), 6.96-7.33 (6H, m), 7.33-7.50 (1H, m), 7.69-7.97 (2H, m), 8.41-8.52 (1H, m), 8.62-8.78 (1H, m), 8.85-8.93 (1H, m).

Example 125 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide

Sodium iodide (2.93 g) was added to a acetonitrile solution (20 ml) of methanesulfonic acid

2-[[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)propyl]-(2-nitro-benzenesulfonyl)amino]-ethyl ester (4.37 g), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. 4-(pyridin-3-ylmethoxy)piperidine (1.87 g) and N-ethyl diisopropylamine (4.23 ml) were then added to the reaction mixture and stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was washed with water, and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure to give the title compound (3.48 g) as a yellow solid.

1H-NMR (CDCl3) δppm: 1.55-1.74 (2H, m), 1.82-1.99 (2H, m), 2.04-2.29 (4H, m), 2.50-2.61 (2H, m), 2.69-2.82 (2H, m), 3.35-3.52 (3H, m), 3.52-3.68 (2H, m), 3.70 (3H, s), 4.01 (2H, t, J=5.9 Hz), 4.54 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.32 (2H, m), 7.55-7.70 (5H, m), 8.04-8.13 (1H, m), 8.53 (1H, dd, J=4.8, 1.7 Hz), 8.57 (1H, d, J=1.7 Hz).

Example 126 Synthesis of 1-methyl-6-{5-[N-(3-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.33-1.51 (2H, m), 1.69-1.99 (4H, m), 2.32 (3H, s), 2.96-3.15 (2H, m), 3.29-3.50 (4H, m), 3.60 (3H, s), 3.95-4.10 (2H, m), 4.26-4.50 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.21-7.38 (4H, m), 7.43-7.55 (3H, m), 7.85 (1H, d, J=9.5 Hz), 8.01 (1H, dd, J=8.0, 5.6 Hz), 8.48 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.93 (1H, s).

Example 127 Synthesis of 1-methyl-6-{5-[N-(4-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.35-1.54 (2H, m), 1.66-2.00 (4H, m), 2.32 (3H, s), 2.94-3.11 (2H, m), 3.28-3.51 (4H, m), 3.60 (3H, s), 4.03 (2H, t, J=6.3 Hz), 4.24-4.50 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.19-7.34 (4H, m), 7.46 (1H, d, J=9.1 Hz), 7.59 (2H, d, J=8.0 Hz), 7.85 (1H, d, J=9.5 Hz), 8.04 (1H, dd, J=8.1, 5.5 Hz), 8.53 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.5 Hz), 8.95 (1H, s).

Example 128 Synthesis of 6-{5-[N-(2-methoxybenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.33-1.51 (2H, m), 1.68-1.97 (4H, m), 2.96-3.20 (2H, m), 3.28-3.49 (2H, m), 3.59 (3H, s), 3.85 (3H, s), 3.95-4.09 (2H, m), 4.25-4.50 (2H, m), 6.61 (1H, d, J=9.5 Hz), 6.98-7.06 (1H, m), 7.09-7.16 (1H, m), 7.24 (1H, dd, J=9.1, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.42-7.50 (2H, m), 7.61-7.69 (1H, m), 7.84 (1H, d, J=9.5 Hz), 7.97-8.06 (1H, m), 8.42 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=5.3 Hz), 8.93 (1H, s).

Example 129 Synthesis of 6-{5-[N-(2-chlorobenzyl)-N-(2-pyridin-3-ylethyl)amino]pentyloxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.36-1.55 (2H, m), 1.69-2.00 (4H, m), 3.05-3.22 (2H, m), 3.34-3.64 (4H, m), 3.59 (3H, s), 4.03 (2H, t, J=6.3 Hz), 4.46-4.72 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.40-7.55 (3H, m), 7.55-7.64 (1H, m), 7.84 (1H, d, J=9.5 Hz), 7.96-8.09 (2H, m), 8.49 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.6 Hz), 8.93 (1H, s).

Example 130 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.84-2.00 (2H, m), 2.79 (2H, t, J=6.7 Hz), 2.84-2.96 (4H, m), 3.71 (3H, s), 3.85 (2H, t, J=6.0 Hz), 4.10 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.77 (1H, d, J=2.8 Hz), 6.98 (1H, dd, J=9.2, 2.8 Hz), 7.09-7.16 (1H, m), 7.24 (1H, d, J=9.2 Hz), 7.33 (1H, d, J=4.4 Hz), 7.35-7.45 (2H, m), 7.57 (1H, d, J=9.5 Hz), 7.57-7.66 (1H, m), 8.00-8.11 (2H, m), 8.41-8.47 (2H, m), 8.74 (1H, d, J=4.4 Hz).

Example 131 Synthesis of 1-methyl-6-{2-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 2.72-2.86 (2H, m), 2.86-3.01 (2H, m), 3.01-3.15 (2H, m), 3.69 (3H, s), 4.00-4.14 (2H, m), 4.22 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.89 (1H, d, J=2.8 Hz), 7.03-7.13 (2H, m), 7.26 (1H, d, J=9.2 Hz), 7.33-7.48 (3H, m), 7.55 (1H, d, J=9.5 Hz), 7.64-7.72 (1H, m), 8.05-8.15 (2H, m), 8.38 (1H, dd, J=4.7, 1.8 Hz), 8.43 (1H, d, J=1.8 Hz), 8.79 (1H, d, J=4.4 Hz).

Example 132 Synthesis of 1-methyl-6-[3-N-(pyridin-3-ylmethyl)-N-(quinolin-4-ylmethyl)amino]propoxy]-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.93-2.25 (2H, m), 2.63-3.08 (2H, m), 3.62 (3H, s), 3.85-4.79 (6H, m), 6.61 (1H, d, J=9.5 Hz), 6.99 (1H, dd, J=9.2, 2.5 Hz), 7.07 (1H, d, J=2.5 Hz), 7.40 (1H, d, J=9.2 Hz), 7.79 (1H, d, J=9.5 Hz), 7.85-8.08 (3H, m), 8.19-8.36 (1H, m), 8.33 (1H, d, J=8.4 Hz), 8.41-8.52 (1H, m), 8.58-8.71 (1H, m), 8.83 (1H, d, J=5.4 Hz), 8.95-9.07 (1H, m), 9.16 (1H, d, J=5.4 Hz).

Example 133 Synthesis of N-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)ethyl]-2-nitro-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.52-1.79 (2H, m), 1.79-1.98 (2H, m), 2.11-2.29 (2H, m), 2.59 (2H, t, J=6.8 Hz), 2.67-2.81 (2H, m), 3.35-3.49 (1H, m), 3.57 (2H, t, J=6.8 Hz), 3.70 (3H, s), 3.81 (2H, t, J=5.5 Hz), 4.21 (2H, t, J=5.5 Hz), 4.53 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.09 (1H, dd, J=9.1, 2.8 Hz), 7.25-7.32 (2H, m), 7.58 (1H, d, J=9.5 Hz), 7.62-7.72 (4H, m), 8.10-8.16 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz), 8.57 (1H, d, J=1.6 Hz).

Example 134 Synthesis of 1-methyl-6-[3-[N-(2-methylbenzyl)-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}amino]propoxy]-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.70-2.40 (6H, m), 2.45 (3H, s), 2.78-3.95 (11H, m), 3.60 (3H, s), 4.01-4.19 (2H, m), 4.38-4.60 (2H, m), 4.71 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.3, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.21-7.39 (3H, m), 7.47 (1H, d, J=9.3 Hz), 7.61-7.78 (1H, m), 7.84 (1H, d, J=9.5 Hz), 7.85-7.99 (1H, m), 8.30-8.48 (1H, m), 8.80 (1H, d, J=4.7 Hz), 8.76-8.94 (1H, m).

Example 135 Synthesis of 1-methyl-6-[3-[N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-3-ylmethyl)amino]propoxy]-1H-quinolin-2-one tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.79-2.47 (6H, m), 3.01-3.98 (11H, m), 3.60 (3H, s), 3.98-4.21 (2H, m), 4.73 (2H, s), 4.78 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.2, 2.9 Hz), 7.32 (1H, d, J=2.9 Hz), 7.48 (1H, d, J=9.2 Hz), 7.87 (1H, d, J=9.5 Hz), 8.04-8.14 (2H, m), 8.55-8.70 (1H, m), 8.87-9.04 (4H, m), 9.30 (1H, s).

Example 136 Synthesis of 1-methyl-6-[3-[N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-4-ylmethyl)amino]propoxy]-1H-quinolin-2-one tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.79-2.35 (6H, m), 2.90-3.95 (11H, m), 3.60 (3H, s), 3.95-4.15 (2H, m), 4.40-4.69 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.5 Hz), 7.28 (1H, d, J=2.5 Hz), 7.46 (1H, d, J=9.1 Hz), 7.86 (1H, d, J=9.5 Hz), 7.96-8.12 (1H, m), 8.33 (2H, s), 8.60 (1H, d, J=7.1 Hz), 8.83-9.01 (4H, m).

Example 137 Synthesis of 1-methyl-6-[2-(N-(2-methylbenzyl)-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}amino)ethoxy]-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.75-2.29 (4H, m), 2.46 (3H, s), 2.92-3.95 (11H, m), 3.61 (3H, s), 4.38-4.69 (4H, m), 4.75 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.23-7.42 (5H, m), 7.50 (1H, d, J=9.0 Hz), 7.73-7.85 (1H, m), 7.84 (1H, d, J=9.5 Hz), 8.06 (1H, dd, J=7.5, 5.6 Hz), 8.56 (1H, d, J=7.5 Hz), 8.87 (1H, d, J=5.6 Hz), 8.94 (1H, s).

Example 138 Synthesis of 1-methyl-6-[2-(N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-3-ylmethyl)amino)ethoxy]-1H-quinolin-2-one tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.59-1.74 (2H, m), 1.83-1.99 (2H, m), 2.09-2.25 (2H, m), 2.46-2.60 (2H, m), 2.70-2.85 (4H, m), 2.94-3.06 (2H, m), 3.39-3.50 (1H, m), 3.69 (3H, s), 3.78 (2H, s), 4.08 (2H, t, J=5.7 Hz), 4.54 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.20-7.31 (3H, m), 7.58 (1H, d, J=9.5 Hz), 7.65-7.76 (2H, m), 8.49 (1H, dd, J=4.8, 1.7 Hz), 8.52 (1H, dd, J=4.8, 1.7 Hz), 8.57 (1H, d, J=1.7 Hz), 8.60 (1H, d, J=1.7 Hz).

Example 139 Synthesis of 1-methyl-6-[2-(N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-4-ylmethyl)amino)ethoxy]-1H-quinolin-2-one tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.55-1.74 (2H, m), 1.82-1.96 (2H, m), 2.08-2.22 (2H, m), 2.45-2.57 (2H, m), 2.65-2.89 (4H, m), 2.98 (2H, t, J=5.7 Hz), 3.35-3.49 (1H, m), 3.69 (3H, s), 3.79 (2H, s), 4.09 (2H, t, J=5.7 Hz), 4.54 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.95 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.36 (4H, m), 7.58 (1H, d, J=9.5 Hz), 7.68 (1H, dt, J=7.8, 1.7 Hz), 8.48-8.55 (3H, m), 8.57 (1H, d, J=1.7 Hz).

Example 140 Synthesis of 6-[4-(N,N-bis-(pyridin-3-ylmethyl)amino)butoxy]-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.60-1.80 (2H, m), 1.80-2.05 (2H, m), 2.80-3.18 (2H, m), 3.60 (3H, s), 3.69-4.71 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.79-7.91 (2H, m), 7.85 (1H, d, J=9.5 Hz), 8.58 (2H, d, J=8.0 Hz), 8.82 (2H, d, J=4.4 Hz), 9.03 (2H, s).

Example 141 Synthesis of 6-[4-(N,N-bis-(pyridin-4-ylmethyl)amino)butoxy]-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.64-1.88 (4H, m), 2.58-2.82 (2H, m), 3.60 (3H, s), 3.88-4.05 (2H, m), 4.19 (4H, s), 6.61 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.24 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.19 (4H, d, J=5.6 Hz), 8.90 (4H, d, J=5.6 Hz).

Example 142 Synthesis of 1-methyl-6-{4-[N-(2-methylbenzyl)-N-(pyridin-3-ylmethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.62-1.80 (2H, m), 1.92-2.14 (2H, m), 2.33 (3H, s), 3.00-3.25 (2H, m), 3.60 (3H, s), 3.90-4.78 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.13-7.35 (5H, m), 7.48 (1H, d, J=9.2 Hz), 7.63-7.79 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.79-7.92 (1H, m), 8.59-8.75 (1H, m), 8.83 (1H, s), 9.02-9.20 (1H, m).

Example 143 Synthesis of 1-methyl-6-{4-[N-(2-methylbenzyl)-N-(pyridin-4-ylmethyl)amino]butoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.60-1.80 (2H, m), 1.89-2.15 (2H, m), 2.36 (3H, s), 3.00-3.30 (2H, m), 3.60 (3H, s), 3.82-4.82 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.06-7.31 (5H, m), 7.47 (1H, d, J=9.1 Hz), 7.61-7.79 (1H, m), 7.84 (1H, d, J=9.5 Hz), 8.11-8.40 (2H, m), 8.86 (2H, d, J=3.5 Hz).

Example 144 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.55-1.78 (2H, m), 1.78-1.95 (2H, m), 1.95-2.25 (4H, m), 2.55 (2H, t, J=6.8 Hz), 2.65-2.81 (2H, m), 3.32-3.51 (3H, m), 3.58 (2H, t, J=7.2 Hz), 3.71 (3H, s), 4.01 (2H, t, J=5.8 Hz), 4.53 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.30 (3H, m), 7.54-7.64 (4H, m), 8.50-8.61 (1H, m), 8.56 (2H, d, J=6.0 Hz).

Example 145 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzenesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.51-1.74 (2H, m), 1.74-1.97 (2H, m), 2.05-2.29 (4H, m), 2.52 (2H, t, J=6.9 Hz), 2.64-2.78 (2H, m), 3.28 (2H, t, J=7.1 Hz), 3.36-3.50 (3H, m), 3.70 (3H, s), 4.06 (2H, t, J=6.0 Hz), 4.53 (2H, s), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.31 (2H, m), 7.45-7.62 (4H, m), 7.62-7.70 (1H, m), 7.81-7.88 (2H, m), 8.52 (1H, dd, J=4.8, 1.6 Hz), 8.57 (1H, d, J=1.6 Hz).

Example 146 Synthesis of N-[3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}phenylmethanesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.55-1.74 (2H, m), 1.85-2.08 (2H, m), 2.08-2.29 (4H, m), 2.46 (2H, t, J=6.5 Hz), 2.69-2.83 (2H, m), 3.19 (2H, t, J=7.3 Hz), 3.27 (2H, t, J=6.5 Hz), 3.38-3.52 (1H, m), 3.69 (3H, s), 3.97 (2H, t, J=6.1 Hz), 4.39 (2H, s), 4.54 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.97 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.31 (2H, m), 7.34-7.46 (5H, m), 7.58 (1H, d, J=9.5 Hz), 7.67 (1H, dt, J=7.8, 1.8 Hz), 8.52 (1H, dd, J=4.8, 1.7 Hz), 8.57 (1H, d, J=1.7 Hz).

Example 147 Synthesis of 2-methyl-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethyl}benzamide

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.31-2.81 (10H, m), 2.21 (3H, s), 3.04-4.16 (9H, m), 3.58 (3H, s), 4.40-4.60 (2H, m), 6.57 (1H, d, J=9.5 Hz), 6.95-7.50 (8H, m), 7.61-7.88 (2H, m), 8.47 (1H, d, J=3.5 Hz), 8.51 (1H, s).

Example 148 Synthesis of N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)propyl]-2-nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 2.00-2.14 (2H, m), 2.55-2.68 (2H, m), 2.80-3.00 (4H, m), 3.33 (3H, s), 3.50-3.65 (4H, m), 3.94 (2H, t, J=5.8 Hz), 6.66-6.75 (2H, m), 6.87 (1H, d, J=8.6 Hz), 7.20 (1H, dd, J=7.8, 4.8 Hz), 7.50-7.68 (4H, m), 7.97-8.02 (1H, m), 8.41 (1H, d, J=1.6 Hz), 8.46 (1H, dd, J=4.8, 1.6 Hz).

Example 149 Synthesis of 1-methyl-6-[3-(N-(2-methylbenzyl)-N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}amino)propoxy]-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.81-2.39 (6H, m), 2.46 (3H, s), 3.01-3.51 (7H, m), 3.60 (3H, s), 3.63-3.91 (4H, m), 4.01-4.18 (2H, m), 4.30-4.52 (2H, m), 4.84 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.21-7.38 (4H, m), 7.47 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=6.0 Hz), 7.84 (1H, d, J=9.5 Hz), 7.92 (2H, d, J=5.7 Hz), 8.84 (2H, d, J=5.7 Hz).

Example 150 Synthesis of 1-methyl-6-[3-(N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-3-ylmethyl)amino)propoxy]-1H-quinolin-2-one tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.95-2.33 (6H, m), 3.00-3.90 (13H, m), 3.60 (3H, s), 4.00-4.12 (2H, m), 4.87 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.1, 2.9 Hz), 7.28 (1H, d, J=2.9 Hz), 7.47 (1H, d, J=9.1 Hz), 7.79-7.89 (1H, m), 7.85 (1H, d, J=9.5 Hz), 7.96-8.05 (2H, m), 8.56 (1H, d, J=7.9 Hz), 8.82 (1H, d, J=4.0 Hz), 8.89 (2H, d, J=6.6 Hz), 9.05 (1H, s).

Example 151 Synthesis of 1-methyl-6-[3-(N-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethyl}-N-(pyridin-4-ylmethyl)amino)propoxy]-1H-quinolin-2-one tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.82-2.30 (6H, m), 2.78-3.90 (13H, m), 3.60 (3H, s), 4.00-4.18 (2H, m), 4.87 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.9 Hz), 7.27 (1H, d, J=2.9 Hz), 7.45 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.02 (2H, d, J=6.4 Hz), 8.15 (2H, d, J=5.3 Hz), 8.86 (2H, d, J=5.3 Hz), 8.89 (2H, d, J=6.4 Hz).

Example 152 Synthesis of 1-methyl-6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.14-2.41 (2H, m), 2.41-2.57 (2H, m), 2.70-2.85 (2H, m), 2.47 (3H, s), 3.21 (3H, s), 3.20-3.39 (2H, m), 3.39-3.62 (4H, m), 3.92-4.08 (2H, m), 4.48 (2H, s), 6.75-6.82 (2H, m), 6.99 (1H, d, J=9.4 Hz), 7.09-7.40 (3H, m), 7.76 (1H, d, J=7.3 Hz), 8.00 (1H, dd, J=8.0, 5.3 Hz), 8.50 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.3 Hz), 8.95 (1H, s).

Example 153 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 2.40-2.61 (2H, m), 2.83 (2H, t, J=6.8 Hz), 3.22 (3H, s), 3.19-3.38 (2H, m), 3.38-3.60 (4H, m), 3.98-4.10 (2H, m), 4.67 (2H, s), 6.76-6.86 (2H, m), 7.00 (1H, d, J=8.8 Hz), 7.92 (1H, dd, J=8.0, 4.9 Hz), 8.02 (1H, dd, J=8.1, 5.4 Hz), 8.54 (1H, d, J=8.1 Hz), 8.74 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.4 Hz), 8.88 (1H, d, J=4.9 Hz), 8.96 (1H, s), 9.18 (1H, s).

Example 154 Synthesis of N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.76-1.95 (2H, m), 2.41-2.58 (2H, m), 2.83 (2H, t, J=7.8 Hz), 3.07 (2H, t, J=7.2 Hz), 3.22 (3H, s), 3.32 (2H, t, J=7.5 Hz), 3.49 (2H, t, J=7.2 Hz), 3.87 (2H, t, J=6.0 Hz), 6.73-6.82 (2H, m), 6.99 (1H, d, J=8.4 Hz), 7.52-7.87 (5H, m), 7.97 (1H, dd, J=8.1, 5.5 Hz), 8.46 (1H, d, J=8.1 Hz), 8.79 (1H, d, J=5.5 Hz), 8.86 (1H, s).

Example 155 Synthesis of 3-{[N-[5-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)pentyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.30-1.52 (2H, m), 1.66-2.00 (4H, m), 2.98-3.19 (2H, m), 3.30-3.50 (4H, m), 3.60 (3H, s), 3.87 (3H, s), 3.95-4.11 (2H, m), 4.43-4.66 (2H, m), 6.61 (1H, d, J=9.5 Hz), 7.24 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.61 (1H, dd, J=7.8, 7.7 Hz), 7.84 (1H, d, J=9.5 Hz), 7.95-8.05 (2H, m), 8.08 (1H, d, J=7.8 Hz), 8.27 (1H, s), 8.48 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=5.2 Hz), 8.94 (1H, s).

Example 156 Synthesis of 3-{[N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.45 (2H, m), 3.28 (2H, t, J=6.9 Hz), 3.37-3.58 (4H, m), 3.60 (3H, s), 3.87 (3H, s), 4.11 (2H, t, J=6.0 Hz), 4.48-4.72 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.62 (1H, dd, J=8.0, 7.7 Hz), 7.83 (1H, d, J=9.5 Hz), 8.02 (1H, d, J=8.0 Hz), 8.05 (1H, dd, J=8.1, 5.5 Hz), 8.13 (1H, d, J=7.7 Hz), 8.29 (1H, s), 8.57 (1H, d, J=8.1 Hz), 8.86 (1H, d, J=5.5 Hz), 8.99 (1H, s).

Example 157 Synthesis of 6-{3-[N-(1H-imidazol-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.21-2.49 (2H, m), 3.20-3.55 (6H, m), 3.60 (3H, s), 4.15 (2H, t, J=6.0 Hz), 4.64 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.2, 2.9 Hz), 7.32 (1H, d, J=2.9 Hz), 7.48 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=9.5 Hz), 8.00 (1H, dd, J=8.0, 5.3 Hz), 8.01 (1H, s), 8.56 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.3 Hz), 8.99 (1H, s), 9.19 (1H, s).

Example 158 Synthesis of 1-methyl-6-{3-[N-(3-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.40 (2H, m), 2.32 (3H, s), 3.12-3.30 (2H, m), 3.30-3.50 (4H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.29-4.57 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.9 Hz), 7.23-7.30 (2H, m), 7.34 (1H, dd, J=7.8, 7.6 Hz), 7.47 (1H, d, J=9.2 Hz), 7.49-7.56 (2H, m), 7.84 (1H, d, J=9.5 Hz), 7.99 (1H, dd, J=8.0, 5.5 Hz), 8.47 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.5 Hz), 8.92 (1H, s).

Example 159 Synthesis of N-(3-imidazol-1-ylpropyl)-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitrobenzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.98-2.20 (4H, m), 3.35 (2H, t, J=6.4 Hz), 3.52 (2H, t, J=7.1 Hz), 3.71 (3H, s), 3.91-4.08 (4H, m), 6.73 (1H, d, J=9.5 Hz), 6.88-6.93 (2H, m), 7.05-7.09 (1H, m), 7.10 (1H, dd, J=9.1, 2.8 Hz), 7.24-7.31 (1H, m), 7.47 (1H, s), 7.55-7.65 (4H, m), 7.93-7.99 (1H, m).

Example 160 Synthesis of 1-methyl-6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-4-ylethyl)amino]propoxy}-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.14-2.40 (2H, m), 2.48 (3H, s), 3.14-3.40 (2H, m), 3.40-4.30 (6H, m), 3.60 (3H, s), 4.30-4.60 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.06-7.39 (5H, m), 7.47 (1H, d, J=9.1 Hz), 7.74 (1H, d, J=8.0 Hz), 7.84 (1H, d, J=9.5 Hz), 7.98 (2H, d, J=5.6 Hz), 8.87 (2H, d, J=5.6 Hz).

Example 161 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-4-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.21-2.42 (2H, m), 3.19-3.39 (2H, m), 3.39-3.60 (4H, m), 3.60 (3H, s), 4.01-4.19 (2H, m), 4.50-4.79 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.23 (1H, d, J=9.0 Hz), 7.28 (1H, s), 7.48 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=9.5 Hz), 7.85-7.95 (1H, m), 8.05 (2H, d, J=5.5 Hz), 8.69 (1H, d, J=6.7 Hz), 8.82-8.93 (3H, m), 9.15 (1H, s).

Example 162 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-4-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.16-2.40 (2H, m), 3.13-3.40 (2H, m), 3.40-3.61 (4H, m), 3.60 (3H, s), 4.00-4.18 (2H, m), 4.58-4.88 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.05 (2H, d, J=6.5 Hz), 8.34 (2H, d, J=5.5 Hz), 8.89 (2H, d, J=6.5 Hz), 8.95 (2H, d, J=5.5 Hz).

Example 163 Synthesis of N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)-N-[3-(quinolin-6-yloxy)propyl]amine trihydrochloride

Sodium iodide (113 mg) was added to a DMF solution (5 ml) of N-(3-chloropropyl)-N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amine (151 mg), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. Potassium carbonate (104 mg) and 6-hydroxyquinoline (87 mg) were then added to the reaction mixture and stirred at 60° C. for 24 hours. The reaction mixture was added to ice water, and the extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution (0.014 ml) was added to a ethyl acetate solution (1 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble product was separated, washed with ether, and dried to give the title compound (7.6 mg) as a brown powder.

1H-NMR (DMSO-D6) δppm: 2.28-2.60 (2H, m), 2.49 (3H, s), 3.20-4.11 (6H, m), 4.27 (2H, t, J=5.6 Hz), 4.36-4.61 (2H, m), 7.22-7.38 (3H, m), 7.63 (1H, dd, J=9.2, 2.5 Hz), 7.68 (1H, d, J=2.5 Hz), 7.74 (1H, d, J=7.9 Hz), 7.87-7.96 (2H, m), 8.26 (1H, d, J=9.2 Hz), 8.39 (1H, d, J=7.9 Hz), 8.78 (1H, d, J=4.3 Hz), 8.84 (1H, d, J=8.8 Hz), 8.88 (1H, s), 9.05 (1H, d, J=5.0 Hz).

Example 164 Synthesis of N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)-N-[3-(pyridin-3-yloxy)propyl]amine trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 163 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.24-2.45 (2H, m), 2.49 (3H, s), 3.18-3.41 (2H, m), 3.41-3.68 (4H, m), 4.32 (2H, t, J=5.8 Hz), 4.37-4.62 (2H, m), 7.20-7.38 (3H, m), 7.78 (1H, d, J=7.4 Hz), 7.94 (1H, dd, J=8.7, 5.4 Hz), 8.04 (1H, dd, J=8.2, 5.7 Hz), 8.07 (1H, dd, J=8.7, 2.3 Hz), 8.52 (1H, d, J=5.4 Hz), 8.55 (1H, d, J=8.2 Hz), 8.62 (1H, d, J=2.3 Hz), 8.85 (1H, d, J=5.5 Hz), 8.97 (1H, s).

Example 165 Synthesis of 1-methyl-6-{3-[N-(3-methylpyridin-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.46 (2H, m), 2.58 (3H, s), 3.20-3.62 (6H, m), 3.61 (3H, s), 4.05-4.20 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=9.5 Hz), 8.05 (1H, dd, J=8.0, 5.6 Hz), 8.60 (1H, d, J=8.0 Hz), 8.51-8.67 (1H, m), 8.86 (1H, d, J=5.6 Hz), 8.82-8.92 (2H, m), 9.00 (1H, s).

Example 166 Synthesis of 1-methyl-6-{3-[N-(3-methylpyridin-4-ylmethyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.04-2.36 (2H, m), 2.52 (3H, s), 2.83 (2H, t, J=7.9 Hz), 3.10-3.60 (6H, m), 3.22 (3H, s), 3.64-4.85 (6H, m), 6.72-6.81 (2H, m), 6.99 (1H, d, J=9.2 Hz), 8.00 (1H, dd, J=8.1, 5.5 Hz), 8.51 (1H, d, J=8.1 Hz), 8.69-8.84 (3H, m), 8.82 (1H, d, J=5.5 Hz), 8.92 (1H, s).

Example 167 Synthesis of 6-{3-[N-(3-imidazol-1-ylpropyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.17-2.60 (4H, m), 2.98-3.35 (4H, m), 3.60 (3H, s), 4.09 (2H, t, J=6.4 Hz), 4.32 (2H, t, J=7.2 Hz), 4.59 (2H, s), 6.63 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.71 (1H, s), 7.78-7.89 (2H, m), 8.15 (2H, d, J=5.9 Hz), 8.86 (2H, d, J=5.9 Hz), 9.23 (1H, s).

Example 169 Synthesis of N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)-N-[3-(pyridin-3-yloxy)propyl]amine tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 163 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 3.06-4.10 (6H, m), 4.28 (2H, t, J=5.8 Hz), 4.74 (2H, s), 7.89 (1H, dd, J=8.7, 5.2 Hz), 7.96-8.06 (2H, m), 8.17 (2H, d, J=5.4 Hz), 8.46-8.52 (2H, m), 8.60 (1H, d, J=2.6 Hz), 8.82 (1H, d, J=5.6 Hz), 8.88 (2H, d, J=5.4 Hz), 8.91 (1H, s).

Example 170 Synthesis of 6-{3-[N-(3-hydroxybenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.41 (2H, m), 3.18-3.50 (6H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.24-4.51 (2H, m), 6.62 (1H, d, J=9.5 Hz), 6.88 (1H, dd, J=8.3, 1.1 Hz), 7.07-7.15 (2H, m), 7.19-7.25 (2H, m), 7.28 (1H, d, J=2.9 Hz), 7.47 (1H, d, J=9.2 Hz), 7.80-7.89 (2H, m), 8.30 (1H, d, J=8.0 Hz), 8.74 (1H, dd, J=5.4, 1.4 Hz), 8.83 (1H, d, J=1.4 Hz).

Example 171 Synthesis of 6-{3-[N-(3-hydroxymethylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one dihydrochloride

Sodium borohydride (16.5 mg) was added to a THF solution (4 ml) of 3-{[N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester (192 mg). Methanol (1 ml) was added to the mixture and stirred for 1.5 hour while heated under reflux. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution (0.082 ml) was added to a ethyl acetate solution (1 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (53.4 mg) as a white powder.

1H-NMR (DMSO-D6) δppm: 2.20-2.41 (2H, m), 3.14-3.47 (6H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.30-4.60 (2H, m), 4.53 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.21 (1H, dd, J=9.2, 2.9 Hz), 7.28 (1H, d, J=2.9 Hz), 7.38-7.45 (2H, m), 7.47 (1H, d, J=9.2 Hz), 7.56-7.66 (2H, m), 7.71 (1H, dd, J=8.0, 5.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.13 (1H, d, J=8.0 Hz), 8.67 (1H, dd, J=5.2, 1.5 Hz), 8.73 (1H, d, J=1.5 Hz).

Example 172 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-N-(2-piperidin-1-ylethyl)benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.33-1.50 (2H, m), 1.50-1.61 (4H, m), 2.08-2.19 (2H, m), 2.30-2.46 (4H, m), 2.52 (2H, t, J=6.9 Hz), 3.50 (2H, t, J=6.9 Hz), 3.59 (2H, t, J=7.0 Hz), 3.70 (3H, s), 4.02 (2H, t, J=5.9 Hz), 6.71 (1H, d, J=9.5 Hz), 6.94 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.55-7.66 (4H, m), 8.06-8.14 (1H, m).

Example 173 Synthesis of N-(2-diethylaminoethyl)-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitrobenzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 0.99 (6H, t, J=7.1 Hz), 2.00-2.19 (2H, m), 2.53 (4H, q, J=7.1 Hz), 2.65 (2H, t, J=7.1 Hz), 3.44 (2H, t, J=7.1 Hz), 3.60 (2H, t, J=7.0 Hz), 3.69 (3H, s), 4.02 (2H, t, J=5.9 Hz), 6.70 (1H, d, J=9.5 Hz), 6.94 (1H, d, J=2.8 Hz), 7.12 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=9.2 Hz), 7.54-7.66 (4H, m), 8.02-8.09 (1H, m).

Example 174 Synthesis of N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-[2-(4-methylpiperazin-1-yl)ethyl]-2-nitrobenzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 125 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 2.01-2.19 (2H, m), 2.47 (3H, s), 2.28-2.56 (8H, m), 2.55 (2H, t, J=6.8 Hz), 3.48 (2H, t, J=6.8 Hz), 3.58 (2H, t, J=7.1 Hz), 3.69 (3H, s), 4.02 (2H, t, J=5.9 Hz), 6.69 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.7 Hz), 7.11 (1H, dd, J=9.2, 2.7 Hz), 7.27 (1H, d, J=9.2 Hz), 7.54-7.66 (4H, m), 8.04-8.12 (1H, m).

Example 175 Synthesis of 1-methyl-6-{3-[N-(2-piperidin-1-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.67-2.26 (8H, m), 2.71-3.60 (10H, m), 3.60 (3H, s), 3.98-4.14 (2H, m), 4.19-5.00 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.13 (2H, d, J=5.4 Hz), 8.86 (2H, d, J=5.4 Hz).

Example 176 Synthesis of 6-{3-[N-(2-diethylaminoethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.19 (6H, t, J=7.2 Hz), 1.90-2.10 (2H, m), 2.58-2.82 (2H, m), 2.90-3.30 (4H, m), 3.10 (4H, q, J=7.2 Hz), 3.60 (3H, s), 3.79-4.14 (4H, m), 6.62 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.9 Hz), 7.26 (1H, d, J=2.9 Hz), 7.45 (1H, d, J=9.2 Hz), 7.67 (2H, d, J=5.8 Hz), 7.84 (1H, d, J=9.5 Hz), 8.62 (2H, d, J=5.8 Hz).

Example 177 Synthesis of 1-methyl-6-(3-{N-[2-(4-methylpiperazin-1-yl)ethyl]N-(pyridin-4-ylmethyl)amino}propoxy)-1H-quinolin-2-one tetrahydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.01-2.21 (2H, m), 2.79 (3H, s), 2.87-3.02 (2H, m), 3.11-3.42 (8H, m), 3.42-3.70 (4H, m), 3.60 (3H, s), 4.00-4.14 (2H, m), 4.31 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.3, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.3 Hz), 7.85 (1H, d, J=9.5 Hz), 8.14 (2H, d, J=6.3 Hz), 8.83 (2H, d, J=6.3 Hz).

Example 178 Synthesis of 1-methyl-5-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.10-2.40 (2H, m), 2.40-2.68 (4H, m), 2.95-4.82 (10H, m), 3.23 (3H, s), 6.66-6.77 (2H, m), 7.21 (1H, dd, J=8.3, 8.2 Hz), 7.91 (1H, dd, J=8.0, 5.5 Hz), 7.97-8.08 (2H, m), 8.38 (1H, d, J=8.0 Hz), 8.73-8.82 (3H, m), 8.85 (1H, s).

Example 179 Synthesis of 1-methyl-7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 4 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.08-2.36 (2H, m), 2.78 (2H, t, J=7.9 Hz), 2.97-4.81 (12H, m), 3.22 (3H, s), 6.50-6.58 (2H, m), 7.11 (1H, d, J=8.9 Hz), 7.88 (1H, dd, J=7.9, 5.4 Hz), 7.92-8.04 (2H, m), 8.35 (1H, d, J=7.9 Hz), 8.72-8.86 (4H, m).

Example 180 Synthesis of N-(4-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}phenyl)acetamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 31 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.01 (3H, s), 2.13-2.40 (2H, m), 3.08-3.52 (6H, m), 3.90-4.10 (2H, m), 4.70 (2H, s), 6.83 (2H, d, J=9.0 Hz), 7.49 (2H, d, J=9.0 Hz), 8.01 (1H, dd, J=8.1, 2.6 Hz), 8.24-8.34 (2H, m), 8.52 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=2.6 Hz), 8.89-8.98 (3H, m).

Example 181 Synthesis of N-[4-(1,7-naphthyridin-2-yloxy)butyl]-N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amine dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.70-2.06 (4H, m), 2.99-3.20 (2H, m), 3.20-3.43 (4H, m), 4.33-4.71 (4H, m), 7.29 (1H, d, J=9.0 Hz), 7.64-7.72 (1H, m), 7.89 (2H, d, J=5.8 Hz), 7.94 (1H, d, J=5.5 Hz), 8.10 (1H, d, J=8.0 Hz), 8.36 (1H, d, J=9.0 Hz), 8.51 (1H, d, J=5.5 Hz), 8.63 (1H, d, J=5.1 Hz), 8.68 (2H, d, J=5.8 Hz), 8.70 (1H, s), 9.16 (1H, s).

Example 182 Synthesis of 7-{4-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]butoxy}-3,4-dihydro-1H-1,8-naphthyridin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.59-1.80 (2H, m), 1.80-2.04 (2H, m), 2.39-2.58 (2H, m), 2.78 (2H, t, J=8.0 Hz), 2.95-3.20 (2H, m), 3.20-3.45 (4H, m), 4.16 (2H, t, J=6.1 Hz), 4.51 (2H, s), 6.33 (1H, d, J=8.0 Hz), 7.50 (1H, d, J=8.0 Hz), 7.80 (1H, dd, J=7.9, 5.0 Hz), 7.96 (2H, d, J=5.8 Hz), 8.24 (1H, d, J=7.9 Hz), 8.71 (1H, d, J=5.0 Hz), 8.75 (2H, d, J=5.8 Hz), 8.78 (1H, s), 10.24 (1H, s).

Example 183 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.21-2.42 (2H, m), 3.14-3.45 (4H, m), 3.60 (3H, s), 3.58-4.20 (4H, m), 4.58-4.75 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, d, J=9.4 Hz), 7.24 (1H, s), 7.41-7.59 (4H, m), 7.82 (1H, d, J=9.5 Hz), 7.85-7.94 (2H, m), 8.04 (2H, d, J=5.5 Hz), 8.80 (2H, d, J=5.5 Hz), 8.93 (1H, s).

Example 184 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)isobutyramide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 0.98 (6H, d, J=6.9 Hz), 1.94-2.20 (2H, m), 2.29-2.41 (1H, m), 2.59-3.09 (4H, m), 3.09-3.54 (4H, m), 3.60 (3H, s), 3.92-4.19 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.2 Hz), 7.56 (2H, d, J=4.2 Hz), 7.83 (1H, d, J=9.5 Hz), 7.92 (1H, s), 8.57 (2H, d, J=4.2 Hz).

Example 185 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)nicotinamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.16-2.43 (2H, m), 3.20-3.51 (4H, m), 3.60 (3H, s), 3.69-3.94 (2H, m), 3.94-4.21 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.18 (1H, dd, J=9.0, 2.7 Hz), 7.25 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.0 Hz), 7.77-7.89 (2H, m), 8.31 (2H, d, J=5.5 Hz), 8.65 (1H, d, J=8.0 Hz), 8.83-8.98 (3H, m), 9.25 (1H, s), 9.56 (1H, s).

Example 186 Synthesis of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)carbamoyloxy}acetic acid ethyl ester

Potassium carbonate (1.66 g) was added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g). The mixture was cooled to 0° C., and ethyl bromoacetate (1.16 ml) was added to the mixture and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→10:1). The purified product was condensed under reduced pressure. The residue was recrystallized from ether, and dried to give the title compound (0.55 g) as a white powder.

1H-NMR (CDCl3) δppm: 1.29 (3H, t, J=7.2 Hz), 2.00-2.19 (2H, m), 3.53 (2H, t, J=5.9 Hz), 3.71 (3H, s), 3.95-4.11 (2H, m), 4.23 (2H, q, J=7.2 Hz), 4.46-4.59 (2H, m), 4.63 (2H, s), 6.72 (1H, d, J=9.5 Hz), 6.99 (1H, s), 7.10-7.35 (4H, m), 7.59 (1H, d, J=9.5 Hz), 8.58 (2H, s).

Example 187 Synthesis of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetic acid ethyl ester

Potassium carbonate (1.66 g) and ethyl bromoacetate (1.16 ml) were added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→85:15). The purified product was condensed under reduced pressure to give the title compound (1.28 g) as a orange oil.

1H-NMR (CDCl3) δppm: 1.27 (3H, t, J=7.1 Hz), 1.89-2.04 (2H, m), 2.86 (2H, t, J=6.8 Hz), 3.38 (2H, s), 3.71 (3H, s), 3.84 (2H, s), 4.07 (2H, t, J=6.2 Hz), 4.17 (2H, q, J=7.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.25-7.35 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.48 (2H, d, J=6.0 Hz).

Example 188 Synthesis of 2-methyl-N-(2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 2.33 (3H, s), 3.07-3.45 (4H, m), 3.60 (3H, s), 3.63-3.84 (2H, m), 4.12 (2H, t, J=5.9 Hz), 4.58 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.16-7.29 (4H, m), 7.29-7.41 (2H, m), 7.46 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 7.99 (2H, d, J=6.0 Hz), 8.57 (1H, s), 8.78 (2H, d, J=6.0 Hz).

Example 189 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.81-1.98 (2H, m), 2.51-2.66 (4H, m), 2.98-3.10 (2H, m), 3.50 (2H, s), 3.72 (3H, s), 4.01 (2H, t, J=5.9 Hz), 5.03 (1H, t, J=5.4 Hz), 6.73 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.10-7.18 (3H, m), 7.30 (1H, d, J=9.2 Hz), 7.42-7.47 (2H, m), 7.48-7.55 (1H, m), 7.62 (1H, d, J=9.5 Hz), 7.74-7.94 (2H, m), 8.47 (2H, d, J=5.9 Hz).

Example 190 Synthesis of N-ethyl-2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.00 (3H, t, J=7.2 Hz), 2.09-2.40 (2H, m), 3.00-3.17 (2H, m), 3.17-3.35 (2H, m), 3.60 (3H, s), 3.73 (2H, s), 4.10 (2H, t, J=5.9 Hz), 4.53 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.07 (2H, d, J=6.2 Hz), 8.53 (1H, s), 8.85 (2H, d, J=6.2 Hz).

Example 191 Synthesis of N,N-diethyl-2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}acetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 0.97 (3H, t, J=7.1 Hz), 1.06 (3H, t, J=7.1 Hz), 2.17-2.35 (2H, m), 3.12-3.30 (4H, m), 3.30-3.45 (2H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.8 Hz), 4.29 (2H, s), 4.61 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.2, 2.8 Hz), 7.30 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=9.2 Hz), 7.85 (1H, d, J=9.5 Hz), 8.06 (2H, d, J=5.9 Hz), 8.87 (2H, d, J=5.9 Hz).

Example 192 Synthesis of 2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-phenylacetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.07-2.32 (2H, m), 3.12-3.40 (2H, m), 3.61 (3H, s), 3.90-4.08 (2H, m), 4.08-4.21 (2H, m), 4.60 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.09 (1H, t, J=7.4 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.26 (1H, d, J=2.8 Hz), 7.28-7.37 (2H, m), 7.44 (1H, d, J=9.2 Hz), 7.59 (2H, d, J=7.7 Hz), 7.82 (1H, d, J=9.5 Hz), 8.16 (2H, d, J=6.2 Hz), 8.88 (2H, d, J=6.2 Hz).

Example 193 Synthesis of N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)phenylmethanesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.02-2.38 (2H, m), 2.79-3.56 (6H, m), 3.60 (3H, s), 3.96-4.16 (2H, m), 4.40-4.72 (2H, m), 4.41 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.7 Hz), 7.27 (1H, d, J=2.7 Hz), 7.31-7.41 (5H, m), 7.47 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.01 (2H, d, J=5.8 Hz), 8.81 (2H, d, J=5.8 Hz).

Example 194 Synthesis of 1-methyl-6-{3-[N-(pyridin-4-ylmethyl)-N-(3-pyridin-3-ylpropyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.10-2.40 (4H, m), 2.75-2.92 (2H, m), 3.00-3.16 (2H, m), 3.16-3.31 (2H, m), 3.60 (3H, s), 4.10 (2H, t, J=5.8 Hz), 4.50 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.19 (1H, dd, J=9.1, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.84 (1H, d, J=9.5 Hz), 7.83-8.09 (3H, m), 8.34 (1H, d, J=7.9 Hz), 8.64-9.02 (4H, m).

Example 195 Synthesis of 2-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-2,3-dihydroisoindol-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.19-2.40 (2H, m), 3.07 (3H, s), 3.13-3.33 (2H, m), 3.33-3.53 (4H, m), 4.12 (2H, t, J=5.8 Hz), 4.39 (2H, s), 4.66 (2H, s), 7.09 (1H, dd, J=8.2, 2.3 Hz), 7.14 (1H, d, J=2.3 Hz), 7.48 (1H, d, J=8.2 Hz), 7.99 (1H, dd, J=8.1, 5.2 Hz), 8.22 (2H, d, J=5.0 Hz), 8.50 (1H, d, J=8.1 Hz), 8.82 (1H, d, J=5.2 Hz), 8.89 (2H, d, J=5.0 Hz), 8.92 (1H, s).

Example 196 Synthesis of 7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.80-2.04 (2H, m), 2.63-2.86 (6H, m), 3.66 (2H, s), 4.08 (2H, t, J=6.0 Hz), 6.54 (1H, d, J=7.1 Hz), 7.07 (1H, d, J=6.5 Hz), 7.15 (2H, d, J=5.9 Hz), 7.15-7.24 (2H, m), 7.39-7.46 (1H, m), 7.49 (1H, d, J=8.7 Hz), 7.77 (1H, d, J=2.6 Hz), 8.39-8.45 (3H, m), 8.47 (1H, dd, J=4.8, 1.6 Hz), 10.96 (1H, s).

Example 197 Synthesis of 2-methyl-7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.13-2.40 (2H, m), 3.00-3.40 (6H, m), 3.51 (3H, s), 4.13 (2H, t, J=5.6 Hz), 4.48 (2H, s), 6.58 (1H, d, J=7.3 Hz), 7.25 (1H, dd, J=8.7, 2.6 Hz), 7.35 (1H, d, J=7.3 Hz), 7.56-7.65 (2H, m), 7.75 (1H, dd, J=7.9, 5.3 Hz), 7.90 (2H, d, J=5.2 Hz), 8.20 (1H, d, J=7.9 Hz), 8.68 (1H, d, J=5.3 Hz), 8.70-8.78 (3H, m).

Example 198 Synthesis of 3-methyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3H-quinazolin-4-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.43 (2H, m), 3.05-3.60 (6H, m), 3.52 (3H, s), 4.10-4.30 (2H, m), 4.65 (2H, s), 7.40 (1H, dd, J=8.9, 2.8 Hz), 7.52 (1H, d, J=2.8 Hz), 7.67 (1H, d, J=8.9 Hz), 7.99 (1H, dd, J=8.0, 5.3 Hz), 8.21 (2H, d, J=5.8 Hz), 8.43 (1H, s), 8.49 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.3 Hz), 8.89 (2H, d, J=5.8 Hz), 8.92 (1H, s).

Example 199 Synthesis of 2-methyl-7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.16-2.39 (2H, m), 2.90 (2H, t, J=6.6 Hz), 3.02 (3H, s), 3.10-3.46 (6H, m), 3.52 (2H, t, J=6.6 Hz), 3.97-4.12 (2H, m), 4.59 (2H, s), 6.98 (1H, dd, J=8.3, 2.7 Hz), 7.21 (1H, d, J=8.3 Hz), 7.35 (1H, d, J=2.7 Hz), 7.92 (1H, dd, J=8.0, 5.5 Hz), 8.07 (2H, d, J=6.1 Hz), 8.40 (1H, d, J=8.0 Hz), 8.77 (1H, d, J=5.5 Hz), 8.81 (2H, d, J=6.1 Hz), 8.86 (1H, s).

Example 200 Synthesis of 7-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.18-2.41 (2H, m), 2.82 (2H, t, J=6.6 Hz), 3.12-3.60 (8H, m), 4.00-4.18 (2H, m), 4.72 (2H, s), 7.00 (1H, dd, J=8.4, 2.7 Hz), 7.23 (1H, d, J=8.4 Hz), 7.34 (1H, d, J=2.7 Hz), 7.96 (1H, s), 8.02 (1H, dd, J=8.0, 5.7 Hz), 8.23-8.38 (2H, m), 8.53 (1H, d, J=8.0 Hz), 8.83 (1H, d, J=5.7 Hz), 8.89-8.99 (3H, m).

Example 201 Synthesis of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.23 (3H, t, J=7.1 Hz), 2.05-2.39 (2H, m), 2.91-3.52 (6H, m), 3.97-4.21 (2H, m), 4.17 (2H, q, J=7.1 Hz), 4.46 (2H, s), 6.99-7.07 (1H, m), 7.11 (1H, d, J=8.4 Hz), 7.49-7.58 (1H, m), 7.65 (1H, dd, J=7.7, 1.7 Hz), 7.71 (1H, dd, J=7.5, 5.6 Hz), 7.79-7.93 (2H, m), 8.14 (1H, d, J=7.5 Hz), 8.62-8.76 (4H, m).

Example 202 Synthesis of 3-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.32 (3H, t, J=7.1 Hz), 2.10-2.40 (2H, m), 2.94-3.60 (6H, m), 4.00-4.18 (2H, m), 4.32 (2H, q, J=7.1 Hz), 4.50 (2H, s), 7.11-7.24 (1H, m), 7.40 (1H, s), 7.37-7.49 (1H, m), 7.56 (1H, d, J=7.7 Hz), 7.81 (1H, dd, J=7.8, 5.4 Hz), 7.83-8.00 (2H, m), 8.25 (1H, d, J=7.8 Hz), 8.64-8.84 (4H, m).

Example 203 Synthesis of 4-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.31 (3H, t, J=7.1 Hz), 2.12-2.41 (2H, m), 3.02-3.60 (6H, m), 4.00-4.20 (2H, m), 4.28 (2H, q, J=7.1 Hz), 4.41-4.74 (2H, m), 6.99 (2H, d, J=8.8 Hz), 7.89 (1H, dd, J=7.7, 5.8 Hz), 7.91 (2H, d, J=8.8 Hz), 7.99 (2H, d, J=5.8 Hz), 8.36 (1H, d, J=7.7 Hz), 8.76 (1H, d, J=5.8 Hz), 8.79 (2H, d, J=5.8 Hz), 8.84 (1H, s).

Example 204 Synthesis of N-ethyl-2-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.05 (3H, t, J=7.2 Hz), 2.20-2.42 (2H, m), 3.08-3.60 (8H, m), 4.07-4.26 (2H, m), 4.52-4.82 (2H, m), 7.02 (1H, dd, J=7.6, 7.5 Hz), 7.09 (1H, d, J=8.2 Hz), 7.39-7.48 (1H, m), 7.59 (1H, dd, J=7.6, 1.7 Hz), 7.99 (1H, dd, J=8.0, 5.2 Hz), 8.07 (1H, s), 8.22 (2H, d, J=5.0 Hz), 8.49 (1H, d, J=8.0 Hz), 8.82 (1H, d, J=5.2 Hz), 8.88 (2H, d, J=5.0 Hz), 8.92 (1H, s).

Example 205 Synthesis of N,N-diethyl-2-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 0.91 (3H, t, J=7.1 Hz), 1.06 (3H, t, J=7.1 Hz), 2.01-2.41 (2H, m), 3.01 (4H, q, J=7.1 Hz), 2.97-3.59 (6H, m), 3.94-4.19 (2H, m), 4.38-4.74 (2H, m), 6.99 (1H, dd, J=7.4, 7.3 Hz), 7.05 (1H, d, J=8.3 Hz), 7.12 (1H, dd, J=7.4, 1.7 Hz), 7.31-7.40 (1H, m), 7.91 (1H, dd, J=8.0, 5.5 Hz), 8.05 (2H, d, J=5.9 Hz), 8.37 (1H, d, J=8.0 Hz), 8.78 (1H, d, J=5.5 Hz), 8.81 (2H, d, J=5.9 Hz), 8.84 (1H, s).

Example 206 Synthesis of N-ethyl-3-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.12 (3H, t, J=7.2 Hz), 2.10-2.38 (2H, m), 3.00-3.41 (8H, m), 3.99-4.20 (2H, m), 4.42 (2H, s), 7.01 (1H, dd, J=8.0, 2.3 Hz), 7.31-7.49 (3H, m), 7.58 (1H, dd, J=7.7, 5.1 Hz), 7.79 (2H, d, J=5.8 Hz), 7.98 (1H, d, J=7.7 Hz), 8.51 (1H, t, J=5.2 Hz), 8.59 (1H, dd, J=5.1, 1.6 Hz), 8.63 (1H, d, J=1.6 Hz), 8.69 (2H, d, J=5.8 Hz).

Example 207 Synthesis of N,N-diethyl-3-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 0.90-1.25 (6H, m), 2.09-2.38 (2H, m), 2.92-3.59 (10H, m), 3.98-4.16 (2H, m), 4.52 (2H, s), 6.82 (1H, d, J=1.7 Hz), 6.89 (1H, d, J=7.5 Hz), 6.94 (1H, dd, J=8.2, 1.7 Hz), 7.34 (1H, dd, J=8.2, 7.5 Hz), 7.85 (1H, dd, J=8.0, 5.2 Hz), 7.99 (2H, d, J=5.4 Hz), 8.31 (1H, d, J=8.0 Hz), 8.74 (1H, dd, J=5.2, 1.5 Hz), 8.78 (2H, d, J=5.4 Hz), 8.82 (1H, d, J=1.5 Hz).

Example 208 Synthesis of N,N-diethyl-4-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}benzamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.09 (6H, t, J=6.8 Hz), 2.12-2.40 (2H, m), 2.95-3.59 (10H, m), 3.95-4.15 (2H, m), 4.56 (2H, s), 6.92 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.91 (1H, dd, J=8.0, 5.3 Hz), 8.06 (2H, d, J=6.0 Hz), 8.38 (1H, d, J=8.0 Hz), 8.77 (1H, d, J=5.3 Hz), 8.82 (2H, d, J=6.0 Hz), 8.86 (1H, s).

Example 209 Synthesis of 2-methyl-8-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.92-2.10 (2H, m), 2.67-3.00 (6H, m), 2.91 (2H, t, J=6.4 Hz), 3.09 (3H, s), 3.46 (2H, t, J=6.4 Hz), 3.69 (2H, s), 4.00 (2H, t, J=5.9 Hz), 6.75 (1H, d, J=7.3 Hz), 6.79 (1H, d, J=8.5 Hz), 7.09-7.19 (3H, m), 7.31 (1H, dd, J=8.5, 7.3 Hz), 7.44 (1H, d, J=7.6 Hz), 8.35-8.46 (4H, m).

Example 210 Synthesis of N,N-dimethyl-2-(4-{3-[N′-(2-pyridin-3-ylethyl)-N′-(pyridin-4-ylmethyl)amino]propoxy}phenyl)propionamide trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.23 (3H, d, J=6.8 Hz), 2.12-2.35 (2H, m), 2.80 (3H, s), 2.87 (3H, s), 3.00-3.49 (6H, m), 3.90-4.10 (3H, m), 4.56 (2H, s), 6.82 (2H, d, J=8.6 Hz), 7.16 (2H, d, J=8.6 Hz), 7.90 (1H, dd, J=8.0, 5.5 Hz), 8.05 (2H, d, J=5.5 Hz), 8.37 (1H, d, J=8.0 Hz), 8.76 (1H, d, J=5.5 Hz), 8.81 (2H, d, J=5.5 Hz), 8.85 (1H, s).

Example 211 Synthesis of 2-methyl-5-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.06-2.40 (2H, m), 2.67 (2H, t, J=6.7 Hz), 3.00 (3H, s), 3.06-3.42 (6H, m), 3.47 (2H, t, J=6.7 Hz), 3.92-4.16 (2H, m), 4.16-4.78 (2H, m), 7.08 (1H, d, J=8.0 Hz), 7.29 (1H, dd, J=8.2, 8.0 Hz), 7.48 (1H, d, J=8.2 Hz), 7.68 (1H, dd, J=7.7, 5.2 Hz), 7.77-7.89 (2H, m), 8.10 (1H, d, J=7.7 Hz), 8.65 (1H, dd, J=5.2, 1.3 Hz), 8.66-8.75 (3H, m).

Example 212 Synthesis of 1,4-dimethyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.14-2.41 (2H, m), 2.42 (3H, s), 2.96-3.50 (6H, m), 3.58 (3H, s), 4.01-4.22 (2H, m), 4.52 (2H, s), 6.54 (1H, s), 7.16 (1H, d, J=2.5 Hz), 7.21 (1H, dd, J=9.2, 2.5 Hz), 7.47 (1H, d, J=9.2 Hz), 7.82 (1H, dd, J=7.9, 5.6 Hz), 7.96 (2H, d, J=4.8 Hz), 8.29 (1H, d, J=7.9 Hz), 8.72 (1H, d, J=5.6 Hz), 8.76 (2H, d, J=4.8 Hz), 8.81 (1H, s).

Example 213 Synthesis of 1-methyl-6-{3-[N-(2-pyridin-2-ylethyl)-N-(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.22-2.40 (2H, m), 3.20-3.38 (2H, m), 3.46-3.62 (4H, m), 3.60 (3H, s), 4.11 (2H, t, J=5.9 Hz), 4.62 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.22 (1H, dd, J=9.1, 2.8 Hz), 7.29 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.1 Hz), 7.60-7.69 (1H, m), 7.74 (1H, d, J=7.9 Hz), 7.81 (1H, dd, J=7.9, 5.0 Hz), 7.85 (1H, d, J=9.5 Hz), 8.14-8.23 (1H, m), 8.58 (1H, d, J=7.9 Hz), 8.69 (1H, d, J=5.0 Hz), 8.82 (1H, dd, J=5.2, 1.3 Hz), 9.08 (1H, d, J=1.3 Hz).

Example 214 Synthesis of N-benzyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)acetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.99 (3H, s), 2.02-2.31 (2H, m), 2.90-3.45 (4H, m), 3.60 (3H, s), 3.50-3.89 (2H, m), 3.98-4.15 (2H, m), 4.25-4.65 (2H, m), 4.60 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.12-7.42 (7H, m), 7.46 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 7.87 (2H, d, J=5.8 Hz), 8.75 (2H, d, J=5.8 Hz).

Example 215 Synthesis of 1-methyl-6-[3-[N-(pyridin-4-ylmethyl)-N-(quinolin-6-yl)amino]propoxy]-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.10-2.27 (2H, m), 3.60 (3H, s), 3.87 (2H, t, J=7.4 Hz), 4.16 (2H, t, J=5.8 Hz), 5.07 (2H, s), 6.61 (1H, d, J=9.5 Hz), 7.24-7.32 (3H, m), 7.47 (1H, d, J=10.1 Hz), 7.69-7.79 (4H, m), 7.81 (1H, d, J=9.5 Hz), 8.11 (1H, d, J=9.5 Hz), 8.61 (1H, d, J=8.4 Hz), 8.75 (2H, d, J=6.4 Hz), 8.82 (1H, d, J=5.1 Hz).

Example 216 Synthesis of 6-(3-{N-[2-(7-bromo-1-oxo-1H-isoquinolin-2-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.93-2.38 (2H, m), 2.74-3.54 (6H, m), 3.61 (3H, s), 3.79-4.15 (2H, m), 4.39 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.70 (1H, d, J=7.4 Hz), 6.98-7.25 (2H, m), 7.42 (1H, d, J=9.2 Hz), 7.60 (1H, d, J=7.4 Hz), 7.65 (1H, d, J=8.5 Hz), 7.80 (1H, d, J=9.5 Hz), 7.87 (1H, dd, J=8.5, 1.8 Hz), 8.00-8.23 (2H, m), 8.27 (1H, d, J=1.8 Hz), 8.65-8.98 (2H, m).

Example 217 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)phenylmethanesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.82-2.02 (2H, m), 2.54 (2H, t, J=6.7 Hz), 2.62 (2H, t, J=6.7 Hz), 2.67 (3H, s), 2.99 (2H, t, J=6.7 Hz), 3.58 (2H, s), 3.71 (3H, s), 4.04 (2H, t, J=6.2 Hz), 4.22 (2H, s), 6.72 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.22 (2H, d, J=5.9 Hz), 7.23-7.40 (6H, m), 7.61 (1H, d, J=9.5 Hz), 8.46 (2H, d, J=5.9 Hz).

Example 218 Synthesis of 2,4,6,N-tetramethyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.82-2.01 (2H, m), 2.28 (3H, s), 2.56 (6H, s), 2.65 (3H, s), 2.61-2.79 (4H, m), 3.29 (2H, t, J=7.2 Hz), 3.60 (2H, s), 3.71 (3H, s), 4.04 (2H, t, J=6.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.92 (2H, s), 6.99 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.19-7.35 (3H, m), 7.60 (1H, d, J=9.5 Hz), 8.47 (2H, d, J=5.9 Hz).

Example 219 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.92-2.08 (2H, m), 2.67 (3H, s), 2.61-2.80 (4H, m), 3.12 (2H, t, J=6.5 Hz), 3.66 (2H, s), 3.71 (3H, s), 4.11 (2H, t, J=6.2 Hz), 6.72 (1H, d, J=9.5 Hz), 7.04 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.35 (3H, m), 7.43-7.61 (3H, m), 7.63 (1H, d, J=9.5 Hz), 7.74 (2H, d, J=6.0 Hz), 8.48 (2H, d, J=6.0 Hz).

Example 220 Synthesis of 4-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzenesulfonamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.85-2.08 (2H, m), 2.64 (3H, s), 2.60-2.79 (4H, m), 3.09 (2H, t, J=6.6 Hz), 3.66 (2H, s), 3.71 (3H, s), 3.85 (3H, s), 4.11 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.94 (2H, d, J=8.9 Hz), 7.04 (1H, d, J=2.8 Hz), 7.13 (1H, dd, J=9.1, 2.8 Hz), 7.20-7.32 (3H, m), 7.56-7.73 (3H, m), 8.47 (2H, d, J=6.0 Hz).

Example 221 Synthesis of 2-nitro-N-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 2 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.96-2.20 (2H, m), 2.82-3.04 (4H, m), 3.47-3.69 (6H, m), 3.99 (2H, t, J=5.8 Hz), 5.97 (1H, s), 6.62 (1H, d, J=2.4 Hz), 6.74 (1H, dd, J=8.6, 2.4 Hz), 7.20 (1H, dd, J=7.8, 4.8 Hz), 7.49-7.64 (4H, m), 7.94-8.01 (2H, m), 8.42 (1H, d, J=1.7 Hz), 8.46 (1H, dd, J=7.8, 1.7 Hz).

Example 222 Synthesis of 6-{3-[N-(2-methylbenzyl)-N-(2-pyridin-3-ylethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.15-2.42 (2H, m), 2.51 (3H, s), 2.86 (2H, t, J=6.5 Hz), 3.19-3.65 (8H, m), 4.11 (2H, t, J=6.0 Hz), 4.33-4.62 (2H, m), 6.78-6.91 (2H, m), 7.22-7.40 (3H, m), 7.70-7.82 (3H, m), 8.04 (1H, dd, J=8.0, 5.3 Hz), 8.54 (1H, d, J=8.1 Hz), 8.85 (1H, d, J=5.3 Hz), 8.97 (1H, s).

Example 223 Synthesis of 6-{3-[N-(2-pyridin-3-ylethyl)-N-(quinolin-4-ylmethyl)amino]propoxy}-3,4-dihydro-2H-isoquinolin-1-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.10-2.45 (2H, m), 2.84 (2H, t, J=6.4 Hz), 3.10-3.73 (8H, m), 3.95-4.10 (2H, m), 4.91-5.41 (2H, m), 6.70 (1H, s), 6.74 (1H, d, J=8.4 Hz), 7.64-7.80 (2H, m), 7.86-7.98 (1H, m), 7.98-8.12 (2H, m), 8.38 (1H, d, J=8.4 Hz), 8.43-8.69 (2H, m), 8.53 (1H, d, J=8.2 Hz), 8.82 (1H, d, J=5.2 Hz), 8.94 (1H, s), 9.23 (1H, d, J=1.7 Hz).

Example 224 Synthesis of 2-methyl-N-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.82-2.24 (2H, m), 2.08 (3H, s), 2.85 (2H, t, J=6.1 Hz), 2.90-3.51 (6H, m), 3.36 (2H, t, J=6.6 Hz), 3.51-4.04 (2H, m), 6.46-7.30 (7H, m), 7.60-8.08 (2H, s), 8.35-9.00 (2H, m).

Example 225 Synthesis of N-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)benzenesulfonamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 81 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.89-2.09 (2H, m), 2.80-3.04 (4H, m), 3.24-3.45 (4H, m), 3.45-3.60 (2H, m), 3.98 (2H, t, J=5.9 Hz), 5.92 (1H, s), 6.66 (1H, d, J=2.4 Hz), 6.82 (1H, dd, J=8.6, 2.4 Hz), 7.12-7.39 (1H, m), 7.43-7.63 (4H, m), 7.74-7.89 (2H, m), 8.00 (1H, d, J=8.6 Hz), 8.40 (1H, d, J=1.7 Hz), 8.46 (1H, dd, J=7.8, 1.7 Hz).

Example 226 Synthesis of 4-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.10-2.46 (2H, m), 2.99 (3H, s), 3.08-3.49 (4H, m), 3.60 (3H, s), 3.78 (3H, s), 3.74-3.98 (2H, m), 3.98-4.20 (2H, m), 4.62 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.96 (2H, d, J=8.9 Hz), 7.18 (1H, dd, J=8.9, 2.6 Hz), 7.25 (1H, d, J=2.6 Hz), 7.31-7.54 (3H, m), 7.82 (1H, d, J=9.5 Hz), 8.14 (2H, d, J=5.7 Hz), 8.85 (2H, d, J=5.7 Hz).

Example 227 Synthesis of thiophene-3-carboxylic acid methyl-(2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.11-2.38 (2H, m), 3.05 (3H, s), 3.02-3.47 (4H, m), 3.60 (3H, s), 3.47-4.21 (4H, m), 4.56 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.1, 2.6 Hz), 7.25 (1H, d, J=2.6 Hz), 7.20-7.36 (1H, m), 7.46 (1H, d, J=9.1 Hz), 7.60 (1H, dd, J=4.9, 2.9 Hz), 7.82 (1H, d, J=9.5 Hz), 7.80-7.96 (1H, m), 8.03 (2H, d, J=5.2 Hz), 8.80 (2H, d, J=5.2 Hz).

Example 228 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)isobutyramide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 0.99 (6H, d, J=6.7 Hz), 2.11-2.41 (2H, m), 2.75-2.89 (1H, m), 3.05 (3H, s), 3.05-3.41 (4H, m), 3.60 (3H, s), 3.68-3.84 (2H, m), 4.00-4.21 (2H, m), 4.63 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.1, 2.6 Hz), 7.27 (1H, d, J=2.6 Hz), 7.47 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.19 (2H, d, J=5.4 Hz), 8.90 (2H, d, J=5.4 Hz).

Example 229 Synthesis of 2-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.12-2.40 (2H, m), 2.79 (3H, s), 2.71-3.02 (2H, m), 3.10-3.33 (2H, m), 3.59 (3H, s), 3.76 (3H, s), 3.81-4.25 (4H, m), 4.55 (2H, s), 6.58 (1H, d, J=9.5 Hz), 6.90-7.27 (5H, m), 7.27-7.50 (2H, m), 7.78 (1H, d, J=9.5 Hz), 8.12 (2H, d, J=5.0 Hz), 8.81 (2H, d, J=5.0 Hz).

Example 230 Synthesis of 2-fluoro-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.13-2.41 (2H, m), 2.88 (3H, s), 2.76-3.10 (2H, m), 3.10-3.48 (2H, m), 3.59 (3H, s), 3.80-4.05 (2H, m), 4.05-4.21 (2H, m), 4.62 (2H, s), 6.59 (1H, d, J=9.5 Hz), 7.08-7.58 (7H, m), 7.79 (1H, d, J=9.5 Hz), 8.25 (2H, s), 8.86 (2H, s).

Example 231 Synthesis of 3,N-dimethyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.31 (3H, s), 2.21-2.45 (2H, m), 2.95 (3H, s), 3.12-3.49 (4H, m), 3.60 (3H, s), 3.79-4.21 (4H, m), 4.65 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.11-7.40 (6H, m), 7.46 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 8.18 (2H, s), 8.86 (2H, s).

Example 232 Synthesis of benzo[1,3]dioxole-5-carboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.19-2.46 (2H, m), 2.97 (3H, s), 3.05-3.49 (4H, m), 3.60 (3H, s), 3.71-3.94 (2H, m), 3.94-4.20 (2H, m), 4.66 (2H, s), 6.06 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.87-7.12 (3H, m), 7.19 (1H, dd, J=9.1, 2.7 Hz), 7.25 (1H, d, J=2.7 Hz), 7.46 (1H, d, J=9.1 Hz), 7.82 (1H, d, J=9.5 Hz), 8.21 (2H, d, J=5.6 Hz), 8.89 (2H, d, J=5.6 Hz).

Example 233 Synthesis of 2-(3-methoxyphenyl)-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)acetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.09-2.31 (2H, m), 2.78-3.30 (4H, m), 3.03 (3H, s), 3.59 (3H, s), 3.68 (2H, s), 3.72 (3H, s), 3.53-3.89 (2H, m), 3.96-4.19 (2H, m), 4.44 (2H, s), 6.58 (1H, d, J=9.5 Hz), 6.70-6.90 (3H, m), 7.10-7.29 (3H, m), 7.43 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 8.00 (2H, d, J=5.3 Hz), 8.76 (2H, d, J=5.3 Hz).

Example 234 Synthesis of 4,5-dimethylfuran-2-carboxylic acid N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.91 (3H, s), 2.23 (3H, s), 2.13-2.42 (2H, m), 3.04-3.46 (4H, m), 3.17 (3H, s), 3.60 (3H, s), 3.81-4.21 (4H, m), 4.68 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.89 (1H, s), 7.18 (1H, dd, J=9.1, 2.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.26 (2H, d, J=5.1 Hz), 8.92 (2H, d, J=5.1 Hz).

Example 235 Synthesis of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-7,8-dihydro-6H-5-thia-8-aza-benzocyclohepten-9-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.10-2.40 (2H, m), 2.93-3.57 (10H, m), 3.95-4.15 (2H, m), 4.61 (2H, s), 6.97 (1H, dd, J=8.4, 2.7 Hz), 7.03 (1H, d, J=2.7 Hz), 7.40 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.1, 5.4 Hz), 8.11 (2H, s), 8.36 (1H, t, J=6.7 Hz), 8.44 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=5.4 Hz), 8.81-8.96 (3H, m).

Example 236 Synthesis of 1-ethyl-6-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-3,4-dihydro-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 32 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.10 (3H, t, J=7.0 Hz), 2.08-2.30 (2H, m), 2.40-2.54 (2H, m), 2.80 (2H, t, J=7.9 Hz), 3.00-3.45 (6H, m), 3.87 (2H, q, J=7.0 Hz), 3.94-4.11 (2H, m), 4.49 (2H, s), 6.69-6.80 (2H, m), 7.03 (1H, d, J=9.0 Hz), 7.79 (1H, dd, J=8.0, 5.4 Hz), 7.93 (2H, d, J=4.9 Hz), 8.24 (1H, d, J=8.0 Hz), 8.70 (1H, d, J=5.4 Hz), 8.70-8.82 (3H, m).

Example 237 Synthesis of 1-methyl-6-{2-[N-((E)-3-pyridin-4-ylallyl)-N-(pyridin-3-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 3.00 (2H, t, J=5.6 Hz), 3.43 (2H, d, J=2.1 Hz), 3.70 (3H, s), 3.81 (2H, s), 4.13 (2H, t, J=5.6 Hz), 6.46-6.55 (1H, m), 6.53 (1H, d, J=2.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.10-7.35 (5H, m), 7.57 (1H, d, J=9.5 Hz), 7.73 (1H, d, J=5.3 Hz), 8.42-8.58 (3H, m), 8.63 (1H, s).

Example 238 Synthesis of 1-methyl-6-{2-[N-(pyridin-3-ylmethyl)-N-(3-pyridin-3-ylpropyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.07-2.31 (2H, m), 2.70-2.95 (2H, m), 3.03-3.25 (2H, m), 3.40-3.69 (2H, m), 3.61 (3H, s), 4.37-4.68 (4H, m), 6.64 (1H, d, J=9.5 Hz), 7.20-7.42 (2H, m), 7.51 (1H, d, J=9.2 Hz), 7.58-7.72 (1H, m), 7.78-7.99 (2H, m), 8.30-8.50 (2H, m), 8.68-8.80 (2H, m), 8.85 (1H, s), 8.98 (1H, s).

Example 239 Synthesis of 1-methyl-6-{2-[N-(pyridin-4-ylmethyl)-N-(3-pyridin-3-ylpropyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.01-2.31 (2H, m), 2.69-2.90 (2H, m), 2.90-3.22 (2H, m), 3.22-3.55 (2H, m), 3.61 (3H, s), 4.30-4.66 (4H, m), 6.63 (1H, d, J=9.5 Hz), 7.26 (1H, dd, J=9.2, 2.7 Hz), 7.33 (1H, d, J=2.7 Hz), 7.50 (1H, d, J=9.2 Hz), 7.76-7.92 (2H, m), 7.98 (2H, d, J=6.1 Hz), 8.33 (1H, d, J=7.9 Hz), 8.72 (1H, d, J=6.5 Hz), 8.73-8.88 (3H, m).

Example 240 Synthesis of 1-methyl-6-{2-[N-((E)-3-pyridin-3-ylallyl)-N-(pyridin-3-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 3.47-3.68 (2H, m), 3.60 (3H, s), 3.94-4.12 (2H, m), 4.46-4.70 (2H, m), 4.70 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.87-7.08 (2H, m), 7.29-7.54 (3H, m), 7.78-7.94 (3H, m), 8.49 (1H, d, J=8.0 Hz), 8.66 (1H, d, J=8.0 Hz), 8.75 (1H, d, J=5.4 Hz), 8.82 (1H, d, J=5.4 Hz), 9.01 (1H, s), 9.12 (1H, s).

Example 241 Synthesis of 1-methyl-6-{2-[N-((E)-3-pyridin-3-ylallyl)-N-(pyridin-4-ylmethyl)amino]ethoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 3.21-3.48 (2H, m), 3.59 (3H, s), 3.70-3.98 (2H, m), 4.28-4.59 (4H, m), 6.62 (1H, d, J=9.5 Hz), 6.68-6.94 (2H, m), 7.18-7.38 (2H, m), 7.46 (1H, d, J=9.0 Hz), 7.57-7.71 (1H, m), 7.82 (1H, d, J=9.5 Hz), 8.02 (2H, d, J=5.1 Hz), 8.23 (1H, d, J=7.1 Hz), 8.62 (1H, d, J=5.1 Hz), 8.66-8.91 (3H, m).

Example 242 Synthesis of N-methyl-3-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-phenylpropionamide

Sodium ethoxide (34 mg) and 3-chloro-N-methyl-N-phenylpropionamide (148 mg) were added to to a ethanol solution (5 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (161 mg), and stirred at 60° C. for 8.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (5.6 mg) as a colorless oil.

1H-NMR (CDCl3) δppm: 1.80-1.98 (2H, m), 2.26 (2H, t, J=7.3 Hz), 2.53 (2H, t, J=6.5 Hz), 2.81 (2H, t, J=7.3 Hz), 3.24 (3H, s), 3.44 (2H, s), 3.72 (3H, s), 3.98 (2H, t, J=6.0 Hz), 6.73 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.7 Hz), 7.00-7.19 (5H, m), 7.24-7.41 (4H, m), 7.60 (1H, d, J=9.5 Hz), 8.42 (2H, d, J=5.4 Hz).

Example 243 Synthesis of 3-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-o-tolylpropionamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.30 (3H, s), 2.20-2.40 (2H, m), 2.91-3.18 (2H, m), 3.18-3.37 (2H, m), 3.37-3.55 (2H, m), 3.60 (3H, s), 3.93-4.20 (2H, m), 4.66 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.00-7.31 (5H, m), 7.36 (1H, d, J=7.3 Hz), 7.46 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 8.20 (2H, d, J=5.2 Hz), 8.90 (2H, d, J=5.2 Hz), 9.72 (1H, s).

Example 244 Synthesis of N-methyl-3-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}-N-o-tolylpropionamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.18 (3H, s), 2.08-2.42 (2H, m), 2.95-3.19 (2H, m), 3.06 (3H, s), 3.19-3.49 (4H, m), 3.60 (3H, s), 3.93-4.13 (2H, m), 4.48 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.19-7.41 (5H, m), 7.48 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 7.97 (2H, d, J=6.0 Hz), 8.80 (2H, d, J=6.0 Hz).

Example 245 Synthesis of furan-3-carboxylic acid methyl-(2-{N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)amide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.13-2.41 (2H, m), 2.98-3.48 (4H, m), 3.15 (3H, s), 3.60 (3H, s), 3.78-3.98 (2H, m), 3.98-4.20 (2H, m), 4.65 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.74 (1H, s), 7.18 (1H, dd, J=9.1, 2.6 Hz), 7.26 (1H, d, J=2.6 Hz), 7.46 (1H, d, J=9.1 Hz), 7.75 (1H, s), 7.83 (1H, d, J=9.5 Hz), 8.15 (1H, s), 8.20 (2H, d, J=5.2 Hz), 8.89 (2H, d, J=5.2 Hz).

Example 246 Synthesis of N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)-2-thiophen-2-ylacetamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.12-2.49 (2H, m), 3.08 (3H, s), 3.12-3.41 (4H, m), 3.60 (3H, s), 3.65-3.88 (2H, m), 3.97 (2H, s), 4.00-4.16 (2H, m), 4.44-4.93 (2H, m), 6.62 (1H, d, J=9.5 Hz), 6.87-7.02 (2H, m), 7.19 (1H, dd, J=9.2, 2.7 Hz), 7.26 (1H, d, J=2.7 Hz), 7.37 (1H, dd, J=5.0, 1.3 Hz), 7.46 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 8.24 (2H, d, J=5.4 Hz), 8.91 (2H, d, J=5.4 Hz).

Example 247 Synthesis of cyclohexanecarboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.03-1.45 (6H, m), 1.45-1.80 (4H, m), 2.17-2.41 (2H, m), 2.41-2.65 (1H, m), 3.05 (3H, s), 3.08-3.40 (4H, m), 3.60 (3H, s), 3.66-3.82 (2H, m), 4.00-4.20 (2H, m), 4.68 (2H, s), 6.62 (1H, d, J=9.5 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.47 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.26 (2H, d, J=5.5 Hz), 8.94 (2H, d, J=5.5 Hz).

Example 248 Synthesis of 3-methoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.20-2.48 (2H, m), 2.95 (3H, s), 3.13-3.51 (4H, m), 3.60 (3H, s), 3.77 (3H, s), 3.82-4.01 (2H, m), 4.01-4.22 (2H, m), 4.76 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.82-7.09 (3H, m), 7.09-7.40 (3H, m), 7.46 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 8.32 (2H, s), 8.94 (2H, s).

Example 249 Synthesis of 5-methylisoxazole-3-carboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.85-2.09 (2H, m), 2.66 (3H, s), 2.59-2.82 (4H, m), 2.98-3.30 (2H, m), 3.20 (3H, s), 3.64 (2H, s), 3.71 (3H, s), 3.98-4.15 (2H, m), 6.25 (1H, s), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=7.4 Hz), 7.03-7.16 (1H, m), 7.16-7.35 (3H, m), 7.62 (1H, d, J=9.5 Hz), 8.36-8.51 (2H, m).

Example 250 Synthesis of benzo[b]thiophene-3-carboxylic acid N-methyl-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)amide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.15-2.41 (2H, m), 3.03 (3H, s), 3.11-3.51 (4H, m), 3.59 (3H, s), 3.75-4.88 (6H, m), 6.61 (1H, d, J=9.5 Hz), 7.09-7.35 (2H, m), 7.35-7.54 (3H, m), 7.67-7.87 (2H, m), 7.87-8.32 (4H, m), 8.88 (2H, s).

Example 251 Synthesis of 2,4-dimethoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.08-2.32 (2H, m), 2.68-3.00 (2H, m), 2.84 (3H, s), 3.00-3.34 (2H, m), 3.59 (3H, s), 3.75 (3H, s), 3.77 (3H, s), 3.65-4.58 (6H, m), 6.45-6.62 (3H, m), 6.98-7.22 (3H, m), 7.41 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 7.94 (2H, s), 8.71 (2H, s).

Example 252 Synthesis of 2,3-dimethoxy-N-methyl-N-(2-{N′-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N′-(pyridin-4-ylmethyl)amino}ethyl)benzamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 46 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.16-2.40 (2H, m), 2.80 (3H, s), 2.80-3.11 (2H, m), 3.11-3.40 (2H, m), 3.59 (3H, s), 3.70 (3H, s), 3.82 (3H, s), 3.85-4.05 (2H, m), 4.05-4.21 (2H, m), 4.59 (2H, s), 6.58 (1H, d, J=9.5 Hz), 6.64-6.87 (2H, m), 7.00-7.29 (3H, m), 7.43 (1H, d, J=9.0 Hz), 7.78 (1H, d, J=9.5 Hz), 8.20 (2H, s), 8.82 (2H, s).

Example 253 Synthesis of 6-{3-[N-(1-benzoylpiperidin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.78-2.02 (2H, m), 2.02-2.42 (4H, m), 2.63-3.50 (5H, m), 3.59 (3H, s), 3.50-4.90 (6H, m), 6.62 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.0, 2.6 Hz), 7.22 (1H, d, J=2.6 Hz), 7.35-7.56 (6H, m), 7.82 (1H, d, J=9.5 Hz), 8.27 (2H, s), 8.89 (2H, s).

Example 254 Synthesis of 6-(3-{N-[1-(2,3-dihydrobenzofuran-7-carbonyl)piperidin-4-yl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1-methyl-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 50 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.68-1.93 (2H, m), 2.03-2.41 (4H, m), 2.60-3.36 (5H, m), 3.59 (3H, s), 3.62-4.79 (6H, m), 4.04 (2H, t, J=7.1 Hz), 4.56 (2H, t, J=8.6 Hz), 6.62 (1H, d, J=9.5 Hz), 6.89 (1H, dd, J=7.2, 7.1 Hz), 7.09 (1H, d, J=7.2 Hz), 7.16 (1H, dd, J=9.2, 2.7 Hz), 7.22 (1H, d, J=2.7 Hz), 7.31 (1H, d, J=7.1 Hz), 7.45 (1H, d, J=9.2 Hz), 7.82 (1H, d, J=9.5 Hz), 8.28 (2H, s), 8.89 (2H, s).

Example 255 Synthesis of 1-methyl-6-{3-[N-(1-phenylpiperidin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 96 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.91-2.43 (6H, m), 2.63-4.31 (9H, m), 3.60 (3H, s), 4.31-4.83 (2H, m), 6.62 (1H, d, J=9.5 Hz), 6.79-7.39 (7H, m), 7.45 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=9.5 Hz), 8.09 (2H, d, J=5.0 Hz), 8.79 (2H, d, J=5.0 Hz).

Example 256 Synthesis of 1-Methyl-6-(3-{N-[2-(N′-methyl-N′-phenylamino)ethyl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1H-quinolin-2-one trihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 96 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.12-2.33 (2H, m), 2.90 (3H, s), 3.07-3.34 (4H, m), 3.60 (3H, s), 3.34-4.00 (2H, m), 4.00-4.16 (2H, m), 4.57 (2H, s), 6.62 (1H, d, J=9.5 Hz), 6.68 (1H, t, J=7.3 Hz), 6.79 (2H, d, J=7.3 Hz), 7.11-7.23 (3H, m), 7.24 (1H, d, J=2.8 Hz), 7.46 (1H, d, J=9.0 Hz), 7.83 (1H, d, J=9.5 Hz), 8.04 (2H, d, J=4.9 Hz), 8.81 (2H, d, J=4.9 Hz).

Example 257 Synthesis of 6-{3-[N-(1-methoxyisoquinolin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.92-2.17 (2H, m), 3.34 (2H, t, J=6.9 Hz), 3.70 (3H, s), 3.99 (2H, t, J=5.9 Hz), 4.09 (3H, s), 4.26 (2H, s), 6.70 (1H, d, J=9.5 Hz), 6.85 (1H, d, J=2.8 Hz), 7.04 (1H, dd, J=9.1, 2.8 Hz), 7.19-7.35 (3H, m), 7.52 (1H, d, J=9.5 Hz), 7.51-7.62 (1H, m), 7.62-7.74 (1H, m), 7.80 (1H, s), 8.18 (1H, d, J=8.2 Hz), 8.26 (1H, d, J=7.6 Hz), 8.48 (2H, d, J=5.9 Hz).

Example 258 Synthesis of 1-methyl-6-{3-[N-(1-oxo-1,2-dihydroisoquinolin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one

6-{3-[N-(1-Methoxyisoquinolin-4-yl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one (55 mg) was added to a 1N-hydrogen chloride in ethanol solution (5 ml), and stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature. 1N-Sodium hydroxide aqueous solution (5 ml) was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (20.6 mg) as a colorless oil.

1H-NMR (CDCl3) δppm: 1.92-2.14 (2H, m), 3.22 (2H, t, J=6.8 Hz), 3.70 (3H, s), 4.02 (2H, t, J=5.9 Hz), 4.16 (2H, s), 6.71 (1H, d, J=9.5 Hz), 6.89 (1H, d, J=2.8 Hz), 7.01 (1H, s), 7.09 (1H, dd, J=9.1, 2.8 Hz), 7.20-7.33 (3H, m), 7.54 (1H, d, J=9.5 Hz), 7.52-7.67 (1H, m), 7.67-7.80 (1H, m), 8.08 (1H, d, J=8.2 Hz), 8.46 (1H, d, J=7.2 Hz), 8.51 (2H, d, J=5.9 Hz).

Example 259 Synthesis of 1-Methyl-6-(3-{N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-(pyridin-4-ylmethyl)amino}propoxy)-1H-quinolin-2-one dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 5 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 1.79-2.09 (2H, m), 2.60-4.15 (8H, m), 3.61 (3H, s), 4.76 (2H, s), 6.58 (1H, d, J=7.0 Hz), 6.63 (1H, d, J=9.5 Hz), 6.90 (1H, d, J=1.8 Hz), 6.99-7.19 (2H, m), 7.44 (1H, d, J=9.1 Hz), 7.51 (1H, d, J=7.0 Hz), 7.68 (2H, d, J=4.6 Hz), 7.83 (1H, d, J=9.5 Hz), 8.13 (1H, d, J=1.8 Hz), 8.53 (2H, d, J=4.6 Hz).

Example 260 Synthesis of 1-methyl-6-[3-(2-pyridin-3-ylethylamino)propoxy]-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.90-2.06 (2H, m), 2.76-3.00 (6H, m), 3.72 (3H, s), 4.08 (2H, t, J=6.1 Hz), 6.73 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.21 (1H, ddd, J=7.7, 4.8, 0.6 Hz), 7.29 (1H, d, J=9.2 Hz), 7.51-7.57 (1H, m), 7.60 (1H, d, J=9.5 Hz), 8.47 (1H, dd, J=4.8, 1.7 Hz), 8.51 (1H, d, J=1.7 Hz).

Example 261 Synthesis of 1-methyl-6-[4-(2-pyridin-3-ylethylamino)butoxy]-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.58-1.76 (2H, m), 1.76-1.92 (2H, m), 2.71 (2H, t, J=7.2 Hz), 2.78-3.00 (4H, m), 3.70 (3H, s), 4.00 (2H, t, J=6.2 Hz), 6.70 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.15 (1H, dd, J=9.2, 2.8 Hz), 7.22 (1H, dd, J=7.7, 4.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.49-7.56 (1H, m), 7.59 (1H, d, J=9.5 Hz), 8.46 (1H, dd, J=4.8, 1.8 Hz), 8.48 (1H, d, J=1.8 Hz).

Example 262 Synthesis of 1-methyl-6-{3-[(pyridin-3-ylmethyl)amino]propoxy}-1H-quinolin-2-one

3N-Hydrochloric acid (5 ml) was added to a ethanol solution (5 ml) of N-[3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-3-ylmethyl)benzamide (250.1 mg), and stirred for 60 hours while heated under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, washed with ethyl acetate. A saturated sodium hydrogencarbonate aqueous solution was added to the aqueous layer, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure to give the title compound (168 mg) as a colorless oil.

1H-NMR (CDCl3) δppm: 1.93-2.10 (2H, m), 2.86 (2H, t, J=6.8 Hz), 3.71 (3H, s), 3.84 (2H, s), 4.11 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.33 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.65-7.72 (1H, m), 8.50 (1H, dd, J=4.8, 1.7 Hz), 8.58 (1H, d, J=1.7 Hz).

Example 263 Synthesis of 1-methyl-6-[2-(2-pyridin-3-ylethylamino)ethoxy]-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 2.76-2.90 (2H, m), 2.90-3.04 (2H, m), 3.07 (2H, t, J=5.2 Hz), 3.71 (3H, s), 4.12 (2H, t, J=5.2 Hz), 6.72 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.23 (1H, dd, J=7.7, 4.8 Hz), 7.30 (1H, d, J=9.2 Hz), 7.52-7.59 (1H, m), 7.59 (1H, d, J=9.5 Hz), 8.48 (1H, dd, J=4.8, 1.7 Hz), 8.51 (1H, d, J=1.7 Hz).

Example 264 Synthesis of 1-methyl-6-{2-[N-(pyridin-3-ylmethyl)amino]ethoxy}-1H-quinolin-2-one

3-Pyridine carbaldehyde (0.99 ml) and 6-(2-Aminoethoxy)-1-methyl-1H-quinolin-2-one (2.18 g) were added to methanol (50 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (0.757 g) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure to give the title compound (3.063 g) as a yellow oil.

1H-NMR (CDCl3) δppm: 3.06 (2H, t, J=5.0 Hz), 3.71 (3H, s), 3.91 (2H, s), 4.14 (2H, t, J=5.0 Hz), 6.72 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.24-7.33 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.68-7.75 (1H, m), 8.52 (1H, dd, J=4.8, 1.7 Hz), 8.61 (1H, d, J=1.7 Hz).

Example 265 Synthesis of methanesulfonic acid 2-[N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-nitro-benzenesulfonyl)amino]ethyl ester

Methane sulfonyl chloride (1.14 ml) was added to a dichloromethane solution (50 ml) of N-(2-hydroxy-thyl)-N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-2-nitro-benzenesulfonamide (4.52 g) and triethylamine (2.73 ml). The mixture was stirred at room temperature overnight. 1N-Sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was washed with saturated saline, and dried with sodium sulfate. After the organic layer was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure to give the title compound (4.37 g) as a yellow solid.

1H-NMR (CDCl3) δppm: 2.00-2.21 (2H, m), 3.03 (3H, s), 3.63 (2H, t, J=7.6 Hz), 3.71 (3H, s), 3.75 (2H, t, J=5.5 Hz), 4.01 (2H, t, J=6.0 Hz), 4.40 (2H, t, J=5.5 Hz), 6.72 (1H, d, J=9.5 Hz), 6.92 (1H, d, J=2.8 Hz), 7.11 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.56-7.67 (4H, m), 8.02-8.08 (1H, m).

Example 266 Synthesis of 1-methyl-6-(3-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethylamino}propoxy)-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.54-2.24 (8H, m), 2.49 (2H, t, J=6.1 Hz), 2.66-2.90 (6H, m), 3.33-3.50 (1H, m), 3.70 (3H, s), 4.00-4.18 (2H, m), 4.54 (2H, s), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.32 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.63-7.71 (1H, m), 8.53 (1H, dd, J=4.7, 1.5 Hz), 8.57 (1H, d, J=1.5 Hz).

Example 267 Synthesis of 1-methyl-6-(2-{2-[4-(pyridin-3-ylmethoxy)piperidin-1-yl]ethylamino}ethoxy)-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.58-1.85 (2H, m), 1.85-2.02 (2H, m), 2.10-2.25 (2H, m), 2.51 (2H, t, J=6.1 Hz), 2.70-2.85 (4H, m), 3.05 (2H, t, J=5.5 Hz), 3.36-3.50 (1H, m), 3.71 (3H, s), 4.13 (2H, t, J=5.5 Hz), 4.56 (2H, s), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.20 (1H, dd, J=9.2, 2.8 Hz), 7.25-7.33 (2H, m), 7.60 (1H, d, J=9.5 Hz), 7.65-7.72 (1H, m), 8.53 (1H, dd, J=4.8, 1.6 Hz), 8.58 (1H, d, J=1.6 Hz).

Example 268 Synthesis of 1-methyl-6-{4-[(pyridin-4-ylmethyl)amino]butoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.62-1.80 (2H, m), 1.80-2.00 (2H, m), 2.72 (2H, t, J=7.0 Hz), 3.71 (3H, s), 3.83 (2H, s), 4.03 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.32 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.54 (2H, d, J=5.9 Hz).

Example 269 Synthesis of 1-methyl-6-{4-[(pyridin-3-ylmethyl)amino]butoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.60-1.80 (2H, m), 1.80-1.98 (2H, m), 2.72 (2H, t, J=7.0 Hz), 3.71 (3H, s), 3.83 (2H, s), 4.02 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.98 (1H, d, J=2.8 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.33 (2H, m), 7.59 (1H, d, J=9.5 Hz), 7.63-7.71 (1H, m), 8.51 (1H, dd, J=4.7, 1.5 Hz), 8.57 (1H, d, J=1.5 Hz).

Example 270 Synthesis of 1-methyl-6-(3-{2-[4-(pyridin-4-ylmethoxy)piperidin-1-yl]ethylamino}propoxy)-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.54-2.24 (8H, m), 2.49 (2H, t, J=6.0 Hz), 2.62-2.90 (6H, m), 3.30-3.49 (1H, m), 3.70 (3H, s), 4.10 (2H, t, J=6.2 Hz), 4.54 (2H, s), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.7 Hz), 7.19 (1H, dd, J=9.2, 2.7 Hz), 7.20-7.32 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.56 (2H, d, J=5.9 Hz).

Example 272 Synthesis of 1-methyl-6-[3-(2-pyridin-3-ylethylamino)propoxy]-3,4-dihydro-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.82-2.02 (2H, m), 2.55-2.68 (2H, m), 2.78-2.99 (8H, m), 3.33 (3H, s), 3.99 (2H, t, J=6.1 Hz), 6.70 (1H, d, J=2.7 Hz), 6.74 (1H, dd, J=8.6, 2.7 Hz), 6.88 (1H, d, J=8.6 Hz), 7.21 (1H, dd, J=7.8, 4.8 Hz), 7.50-7.57 (1H, m), 8.46 (1H, dd, J=4.8, 1.8 Hz), 8.49 (1H, d, J=1.8 Hz).

Example 273 Synthesis of 1-methyl-6-[3-(2-pyridin-4-ylethylamino)propoxy]-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.92-2.08 (2H, m), 2.77-2.90 (4H, m), 2.90-3.01 (2H, m), 3.71 (3H, s), 4.07 (2H, t, J=6.1 Hz), 6.72 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.8 Hz), 7.09-7.19 (3H, m), 7.29 (1H, d, J=9.3 Hz), 7.59 (1H, d, J=9.5 Hz), 8.50 (2H, d, J=6.0 Hz).

Example 274 Synthesis of 6-[3-(3-imidazol-1-yl-propylamino)propoxy]-1-methyl-1H-quinolin-2-one

3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propionaldehyde (127.5 mg) prepared from 6-hydroxy-1-methylquinolin-2(1H)-one and N-(3-aminopropyl)imidazole (82.9 mg) were added to methanol (10 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (31.4 mg) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (21 mg) as a yellow oil.

1H-NMR (CDCl3) δppm: 1.81-2.02 (4H, m), 2.49-2.58 (2H, m), 2.80 (2H, t, J=6.9 Hz), 3.70 (3H, s), 3.93-4.15 (4H, m), 6.71 (1H, d, J=9.5 Hz), 6.91 (1H, s), 7.01 (1H, d, J=2.8 Hz), 7.05 (1H, s), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.47 (1H, s), 7.60 (1H, d, J=9.5 Hz).

Example 275 Synthesis of 1-methyl-6-[3-(2-piperidin-1-ylethylamino)propoxy]-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.32-1.49 (2H, m), 1.49-1.63 (4H, m), 1.94-2.08 (2H, m), 2.28-2.41 (4H, m), 2.45 (2H, t, J=6.2 Hz), 2.73 (2H, t, J=6.2 Hz), 2.83 (2H, t, J=6.9 Hz), 3.70 (3H, s), 4.10 (2H, t, J=6.2 Hz), 6.70 (1H, d, J=9.5 Hz), 7.01 (1H, d, J=2.8 Hz), 7.18 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).

Example 276 Synthesis of 6-[3-(2-diethylaminoethylamino)propoxy]-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.00 (6H, t, J=7.1 Hz), 1.90-2.08 (2H, m), 2.41-2.60 (6H, m), 2.69 (2H, t, J=5.7 Hz), 2.83 (2H, t, J=6.9 Hz), 3.71 (3H, s), 4.10 (2H, t, J=6.3 Hz), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).

Example 277 Synthesis of 1-methyl-6-{3-[2-(4-methylpiperazin-1-yl)ethylamino]propoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.91-2.08 (2H, m), 2.26 (3H, s), 2.31-2.63 (10H, m), 2.73 (2H, t, J=6.1 Hz), 2.83 (2H, t, J=6.8 Hz), 3.70 (3H, s), 4.10 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.6 Hz), 7.19 (1H, dd, J=9.2, 2.6 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).

Example 278 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}benzamide

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.92-2.10 (2H, m), 2.82-3.00 (4H, m), 3.49-3.61 (2H, m), 3.68 (3H, s), 4.11 (2H, t, J=6.1 Hz), 6.70 (1H, d, J=9.5 Hz), 6.81 (1H, s), 6.97 (1H, d, J=2.8 Hz), 7.14 (1H, dd, J=9.2, 2.8 Hz), 7.23 (1H, d, J=9.2 Hz), 7.31-7.39 (2H, m), 7.41-7.48 (1H, m), 7.54 (1H, d, J=9.5 Hz), 7.70-7.77 (2H, m).

Example 279 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}isobutyramide

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.13 (6H, d, J=6.9 Hz), 1.90-2.08 (2H, m), 2.25-2.41 (1H, m), 2.75-2.90 (4H, m), 3.30-3.42 (2H, m), 3.70 (3H, s), 4.09 (2H, t, J=6.1 Hz), 6.09 (1H, s), 6.71 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.59 (1H, d, J=9.5 Hz).

Example 280 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}nicotinamide

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.90-2.10 (2H, m), 2.80-3.00 (4H, m), 3.49-3.62 (2H, m), 3.68 (3H, s), 4.11 (2H, t, J=6.2 Hz), 6.69 (1H, d, J=9.5 Hz), 6.96 (1H, d, J=2.7 Hz), 7.02 (1H, s), 7.14 (1H, dd, J=9.1, 2.7 Hz), 7.24 (1H, d, J=9.1 Hz), 7.31 (1H, dd, J=7.9, 4.8 Hz), 7.56 (1H, d, J=9.5 Hz), 8.03-8.11 (1H, m), 8.67 (1H, dd, J=4.8, 1.9 Hz), 8.95 (1H, d, J=1.9 Hz).

Example 281 Synthesis of N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}benzenesulfonamide

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.80-1.99 (2H, m), 2.65-2.81 (4H, m), 2.99-3.12 (2H, m), 3.70 (3H, s), 4.05 (2H, t, J=6.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.7 Hz), 7.16 (1H, dd, J=9.1, 2.7 Hz), 7.28 (1H, d, J=9.1 Hz), 7.45-7.63 (4H, m), 7.82-7.90 (2H, m).

Example 282 Synthesis of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetic acid

A 1N-sodium hydroxide aqueous solution (3 ml) was added to a methanol solution (15 ml) of {N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(pyridin-4-ylmethyl)amino}acetic acid ethyl ester (614 mg). The mixture was stirred at room temperature overnight. 1N-Hydrochloric acid (3 ml) was added to the reaction mixture and condensed under reduced pressure. Metanol was added to the residue, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (468 mg) as a white amorphous solid.

1H-NMR (DMSO-D6) δppm: 1.75-1.94 (2H, m), 2.73 (2H, t, J=6.8 Hz), 3.03 (2H, s), 3.59 (3H, s), 3.82 (2H, s), 4.04 (2H, t, J=6.4 Hz), 6.59 (1H, d, J=9.5 Hz), 7.17 (1H, dd, J=9.1, 2.9 Hz), 7.23 (1H, d, J=2.9 Hz), 7.32 (2H, d, J=5.9 Hz), 7.44 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=9.5 Hz), 8.40 (2H, d, J=5.9 Hz).

Example 283 Synthesis of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.86-2.10 (2H, m), 2.70-2.92 (2H, m), 3.71 (3H, s), 3.85 (2H, s), 4.12 (2H, t, J=6.0 Hz), 6.72 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.8 Hz), 7.08-7.38 (4H, m), 7.59 (1H, d, J=9.5 Hz), 8.53 (2H, d, J=5.9 Hz).

Example 284 Synthesis of 6-{3-[(2-aminoethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}-1-methyl-1H-quinolin-2-one

A 4N-hydrogen chloride ethyl acetate solution (0.22 ml) was added to an ethyl acetate solution (3 ml) of (2-{[3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (137 mg), and the mixture was stirred at room temperature overnight. 5N-Ammoia methanol solution (1 ml) was added to the reaction mixture, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (85.7 mg) as an colorless oil.

1H-NMR (CDCl3) δppm: 1.88-2.08 (2H, m), 2.57 (2H, t, J=6.0 Hz), 2.67 (2H, t, J=6.9 Hz), 2.80 (2H, t, J=6.0 Hz), 3.62 (2H, s), 3.71 (3H, s), 4.05 (2H, t, J=6.0 Hz), 6.71 (1H, d, J=9.5 Hz), 6.95 (1H, d, J=2.8 Hz), 7.10 (1H, dd, J=9.2, 2.8 Hz), 7.22-7.32 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.49 (2H, d, J=6.0 Hz).

Example 285 Synthesis of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid

A 1N-sodium hydroxide aqueous solution (1.8 ml) was added to a methanol solution (3 ml) of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester (372 mg). The mixture was stirred at room temperature overnight. 6N-Hydrochloric acid (0.3 ml) was added to the reaction mixture and condensed under reduced pressure. Metanol was added to the residue, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (458 mg) as a colorless oil.

1H-NMR (DMSO-D6) δppm: 2.12-2.38 (2H, m), 3.09-3.48 (6H, m), 4.01-4.19 (2H, m), 4.46 (2H, s), 6.92-7.08 (1H, m), 7.10 (1H, d, J=6.9 Hz), 7.41-7.56 (1H, m), 7.64-7.77 (2H, m), 7.85 (2H, s), 8.13 (1H, d, J=7.6 Hz), 8.65 (1H, dd, J=5.2, 1.2 Hz), 8.68-8.80 (3H, m).

Example 286 Synthesis of 3-{3-[N-(2-pyridin-3-yl-ethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid

The synthesis of the title compound was performed in the same manner as in Example 285 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.10-2.41 (2H, m), 3.02-3.59 (6H, m), 3.98-4.22 (2H, m), 4.43-4.72 (2H, m), 7.19 (1H, d, J=8.3 Hz), 7.31-7.46 (2H, m), 7.54 (1H, d, J=7.7 Hz), 7.63-7.77 (1H, m), 7.83 (2H, s), 8.04-8.20 (1H, m), 8.65 (1H, d, J=5.3 Hz), 8.66-8.79 (3H, m).

Example 287 Synthesis of 4-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid

The synthesis of the title compound was performed in the same manner as in Example 285 using appropriate starting materials.

1H-NMR (DMSO-D6) δppm: 2.16-2.38 (2H, m), 3.00-3.99 (6H, m), 3.99-4.16 (2H, m), 4.35-4.69 (2H, m), 6.96 (2H, d, J=8.8 Hz), 7.62-7.80 (1H, m), 7.80-7.99 (4H, m), 8.19 (1H, d, J=6.7 Hz), 8.60-8.80 (4H, m).

Example 288 Synthesis of 1-methyl-6-[3-(2-pyridin-2-ylethylamino)propoxy]-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.91-2.12 (2H, m), 2.86 (2H, t, J=6.8 Hz), 2.92-3.14 (4H, m), 3.71 (3H, s), 4.07 (2H, t, J=6.2 Hz), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.07-7.25 (3H, m), 7.28 (1H, d, J=9.5 Hz), 7.51-7.68 (2H, m), 8.51 (1H, dd, J=4.8, 0.8 Hz).

Example 289 Synthesis of 1-methyl-6-[3-(quinolin-6-ylamino)propoxy]-1H-quinolin-2-one

6-Aminoquinoline (360 mg) was added to the methanol solution (10 ml) of 6-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one (172 mg) and stirred at 60° C. for 17 hours. The reaction mixture was added to ice water, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (86.4 mg) as a yellow amorphous solid.

1H-NMR (CDCl3) δppm: 2.13-2.29 (2H, m), 3.50 (2H, t, J=6.6 Hz), 3.70 (3H, s), 4.18 (2H, t, J=5.8 Hz), 6.67-6.77 (2H, m), 7.01 (1H, d, J=2.7 Hz), 7.11 (1H, dd, J=9.1, 2.7 Hz), 7.18-7.27 (2H, m), 7.29 (1H, d, J=9.1 Hz), 7.56 (1H, d, J=9.5 Hz), 7.86 (1H, s), 7.89 (1H, s), 8.61 (1H, dd, J=4.2, 1.6 Hz).

Example 290 Synthesis of N-benzyl-N-{2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propylamino]ethyl}acetamide

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.87-2.06 (2H, m), 2.12 (3H, s), 2.70-2.90 (4H, m), 3.51 (2H, t, J=6.5 Hz), 3.71 (3H, s), 3.98-4.15 (2H, m), 4.58 (2H, s), 6.71 (1H, d, J=9.5 Hz), 6.98-7.03 (1H, m), 7.13-7.21 (2H, m), 7.21-7.40 (5H, m), 7.59 (1H, d, J=9.5 Hz).

Example 291 Synthesis of 6-{3-[2-(7-bromo-1-oxo-1H-isoquinolin-2-yl)ethylamino]propoxy}-1-methyl-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.88-2.05 (2H, m), 2.87 (2H, t, J=6.6 Hz), 3.06 (2H, t, J=6.1 Hz), 3.70 (3H, s), 4.04 (2H, t, J=6.1 Hz), 4.12 (2H, t, J=6.1 Hz), 6.37 (1H, d, J=7.3 Hz), 6.71 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.09 (1H, dd, J=9.2, 2.8 Hz), 7.12 (1H, d, J=7.3 Hz), 7.23 (1H, d, J=9.2 Hz), 7.32 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=9.5 Hz), 7.67 (1H, dd, J=8.5, 2.1 Hz), 8.52 (1H, d, J=2.1 Hz).

Example 292 Synthesis of 1-Methyl-6-{3-[(2-methylamino-ethyl)-pyridin-4-ylmethyl-amino]-propoxy}-1H-quinolin-2-one trihydrochloride

A 4N-hydrogen chloride ethyl acetate solution (4.2 ml) was added to an ethyl acetate solution (30 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (1.0 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was condensed under reduced pressure to give the title compound (1.0 g) as a white powder.

1H-NMR (DMSO-D6) δppm: 1.95-2.22 (2H, m), 2.52 (3H, s), 2.56 (2H, t, J=5.4 Hz), 2.77-3.40 (4H, m), 3.61 (3H, s), 3.99-4.16 (2H, m), 4.16-5.10 (2H, m), 6.62 (1H, d, J=9.5 Hz), 7.16 (1H, dd, J=9.2, 2.8 Hz), 7.28 (1H, d, J=2.8 Hz), 7.45 (1H, d, J=9.2 Hz), 7.84 (1H, d, J=9.5 Hz), 8.17 (2H, d, J=5.0 Hz), 8.83 (2H, d, J=5.0 Hz).

Example 293 Synthesis of 1-Methyl-6-{3-[(2-methylamino-ethyl)-pyridin-4-ylmethyl-amino]-propoxy}-1H-quinolin-2-one

A 4N-hydrogen chloride ethyl acetate solution (48 ml) was added to an ethyl acetate solution (300 ml) of methyl-(2-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (11.5 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3 (40 g) was added to the methanol solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure to give the title compound (9.96 g) as a brown oil.

1H-NMR (CDCl3) δppm: 1.88-2.07 (2H, m), 2.43 (3H, s), 2.68 (2H, t, J=6.9 Hz), 2.70-2.88 (4H, m), 3.64 (2H, s), 3.70 (3H, s), 4.04 (2H, t, J=5.9 Hz), 6.71 (1H, d, J=9.5 Hz), 6.97 (1H, d, J=2.8 Hz), 7.10 (1H, dd, J=9.1, 2.8 Hz), 7.20-7.36 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.49 (2H, d, J=6.0 Hz).

Example 294 Synthesis of 6-[3-(2-Pyridin-3-yl-ethylamino)-propoxy]-3,4-dihydro-2H-isoquinolin-1-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.84-2.02 (2H, m), 2.74-2.87 (4H, m), 2.87-3.02 (4H, m), 3.48-3.61 (2H, m), 4.06 (2H, t, J=6.1 Hz), 5.88 (1H, s), 6.66 (1H, d, J=2.4 Hz), 6.81 (1H, dd, J=8.6, 2.4 Hz), 7.20 (1H, dd, J=7.7, 4.8 Hz), 7.47-7.60 (1H, m), 8.00 (1H, d, J=8.6 Hz), 8.46 (1H, dd, J=4.8, 1.8 Hz), 8.49 (1H, d, J=1.8 Hz).

Example 295 Synthesis of 1-Methyl-6-{2-[(pyridin-4-ylmethyl)-amino]-ethoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 264 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 3.05 (2H, t, J=5.2 Hz), 3.71 (3H, s), 3.92 (2H, s), 4.15 (2H, t, J=5.2 Hz), 6.72 (1H, d, J=9.5 Hz), 7.02 (1H, d, J=2.8 Hz), 7.19 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.46 (3H, m), 7.59 (1H, d, J=9.5 Hz), 8.56 (2H, d, J=6.0 Hz).

Example 296 Synthesis of 3-[3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propylamino]-N-o-tolyl-propionamide

Sodium ethoxide (34 mg) was added to an ethanol solution (5 ml) of 6-(3-amino-propoxy)-1-methyl-1H-quinolin-2-one (116 mg) and 3-chloro-N-o-tolyl-propionamide (148 mg). The mixture was stirred at 60° C. for 5 hours. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (115 mg) as a white powder.

1H-NMR (CDCl3) δppm: 2.15-2.36 (2H, m), 2.26 (3H, s), 2.99-3.56 (6H, m), 3.63 (3H, s), 4.11 (2H, t, J=5.6 Hz), 6.66 (1H, d, J=9.5 Hz), 6.92-7.29 (6H, m), 7.47 (1H, d, J=9.5 Hz), 7.59 (1H, d, J=6.9 Hz), 9.25 (1H, s).

Example 297 Synthesis of N-Methyl-3-[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propylamino]-N-o-tolyl-propionamide

6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one (194 mg) was added to an ethanol solution (5 ml) of N-methyl-N-o-tolyl-acrylamide (146 mg). The mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (172.6 mg) as a colorless oil.

1H-NMR (CDCl3) δppm: 2.06-2.25 (2H, m), 2.24 (3H, s), 2.25-2.50 (2H, m), 2.86-3.03 (4H, m), 3.20 (3H, s), 3.70 (3H, s), 4.12 (2H, t, J=6.0 Hz), 6.71 (1H, d, J=9.5 Hz), 7.07 (1H, d, J=2.3 Hz), 7.13 (1H, dd, J=8.3, 2.3 Hz), 7.19-7.38 (5H, m), 7.60 (1H, d, J=9.5 Hz).

Example 298 Synthesis of 1-Methyl-6-[3-(piperidin-4-yl-pyridin-4-ylmethyl-amino)-propoxy]-1H-quinolin-2-one

Trifluoroacetic acid (30 ml) was added to a dichloromethane solution (10 ml) of 4-{[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.08 g), and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. PL-HCO3 (40 g) was added to the dichloromethane solution of the residue and followed by celite filtration. The filtrate was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=4:1). The purified product was condensed under reduced pressure to give the title compound (758 mg) as an orange oil.

1H-NMR (CDCl3) δppm: 1.45-1.65 (2H, m), 1.70-1.99 (4H, m), 2.50-2.69 (3H, m), 2.74 (2H, t, J=6.7 Hz), 3.11-3.25 (2H, m), 3.68 (2H, s), 3.71 (3H, s), 4.00 (2H, t, J=6.0 Hz), 6.72 (1H, d, J=9.5 Hz), 6.93 (1H, d, J=2.8 Hz), 7.10 (1H, dd, J=9.2, 2.8 Hz), 7.23-7.35 (3H, m), 7.60 (1H, d, J=9.5 Hz), 8.47 (2H, d, J=6.0 Hz).

Example 299 Synthesis of 6-[3-(1-Methoxy-isoquinolin-4-ylamino)-propoxy]-1-methyl-1H-quinolin-2-one

6-(3-Amino-propoxy)-1-methyl-1H-quinolin-2-one (232 mg), 4-bromo-1-methoxy-isoquinoline (286 mg), palladium acetate (II)(22 mg), xantphos (558 mg), and sodium t-butoxide (192 mg) were added to dioxane (10 ml). The mixture was heated at 80° C. for overnight under argon atmosphere. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, and followed by celite filtration. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→1:0). The purified product was condensed under reduced pressure to give the title compound (99 mg) as a brown amorphous solid.

1H-NMR (CDCl3) δppm: 2.20-2.37 (2H, m), 3.48 (2H, t, J=6.5 Hz), 3.68 (3H, s), 4.06 (3H, s), 4.22 (2H, t, J=5.9 Hz), 6.69 (1H, d, J=9.5 Hz), 7.00 (1H, d, J=2.7 Hz), 7.13-7.31 (2H, m), 7.39 (1H, s), 7.51-7.62 (2H, m), 7.62-7.73 (1H, m), 7.79 (1H, d, J=8.3 Hz), 8.25 (1H, dd, J=8.3, 0.5 Hz).

Example 300 Synthesis of 1-Methyl-6-{3-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)-ethylamino]-propoxy}-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.87-2.03 (2H, m), 2.86 (2H, t, J=6.7 Hz), 3.06 (2H, t, J=6.2 Hz), 3.70 (3H, s), 4.06 (2H, t, J=6.1 Hz), 4.18 (2H, t, J=6.2 Hz), 6.39 (1H, d, J=7.0 Hz), 6.61 (1H, d, J=2.1 Hz), 6.71 (1H, d, J=9.5 Hz), 6.97 (1H, d, J=2.8 Hz), 7.08-7.19 (2H, m), 7.21-7.32 (1H, m), 7.59 (1H, d, J=9.5 Hz), 7.71 (1H, d, J=2.1 Hz).

Example 301 Synthesis of 1-Methyl-6-[5-(2-pyridin-3-yl-ethylamino)-pentyloxy]-1H-quinolin-2-one

The synthesis of the title compound was performed in the same manner as in Example 3 using appropriate starting materials.

1H-NMR (CDCl3) δppm: 1.44-1.72 (4H, m), 1.72-1.90 (2H, m), 2.67 (2H, t, J=6.9 Hz), 2.74-2.97 (4H, m), 3.71 (3H, s), 4.00 (2H, t, J=6.4 Hz), 6.71 (1H, d, J=9.5 Hz), 6.99 (1H, d, J=2.8 Hz), 7.17 (1H, dd, J=9.2, 2.8 Hz), 7.22 (1H, dd, J=7.8, 4.8 Hz), 7.29 (1H, d, J=9.2 Hz), 7.50-7.56 (1H, m), 7.59 (1H, d, J=9.5 Hz), 8.47 (1H, dd, J=4.8, 1.8 Hz), 8.49 (1H, d, J=1.8 Hz).

Example 302 N-(2-Methyl-benzyl)-4-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-N-{2-[4-(pyridin-3-ylmethoxy)-piperidin-1-yl]-ethyl}-butyramide dihydrochloride

To a DMF solution (3 ml) of 4-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-butyric acid (100 mg) were sequentially added (2-methyl-benzyl)-{2-[4-(pyridin-3-ylmethoxy)-piperidin-1-yl]-ethyl}-amine (143 mg), triethylamine (47 mg), diethylphosphorocyanidate (DEPC, 84 mg) while ice-cooling, followed by stirring at room temperature overnight. Water was added to the reaction mixture and then subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate:methanol:28% ammonia solution=70:20:10:1). The purified product was concentrated under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution was added to a ethyl acetate solution of the residue. The mixture was condensed under reduced pressure to give the title compound (165 mg) as a pale yellow amorphous solid.

1H-NMR (DMSO-d6) δppm: 1.79-2.60 (8H, m), 2.24, 2.28 (total 3H, each-s), 2.68-4.28 (11H, m), 3.58 (3H, s), 4.45-4.76 (4H, m), 6.59, 6.60 (total 1H, each-d, J=9.5 Hz), 6.82-7.50 (7H, m), 7.75-7.88 (1H, m), 7.88-8.00 (1H, m), 8.35-8.50 (1H, m), 8.72-8.95 (2H, m).

Example 303 N-(2-Methyl-benzyl)-4-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-N-(2-pyridin-3-yl-ethyl)-butyramide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 302 using appropriate starting materials.

1H-NMR (DMSO-d6) δppm: 1.80-2.08 (2H, m), 2.23, 2.27 (total 3H, each-s), 2.29-2.63 (2H, m), 2.96-3.14 (2H, m), 3.59 (3H, s), 3.48-3.70 (2H, m), 3.93, 4.04 (total 2H, each-t, J=6.3 Hz), 4.57, 4.61 (total 2H, each-s), 6.60, 6.61 (total 1H, each-d, J=9.5 Hz), 6.85-7.33 (6H, m), 7.38-7.50 (1H, m), 7.78-7.89 (1H, m), 7.89-8.00 (1H, m), 8.82-8.47 (1H, m), 8.70-8.80 (1H, m), 8.80-8.92 (1H, m).

Example 304 1-[5-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-pentyl]-3-phenyl-1-(2-pyridin-3-yl-ethyl)-urea hydrochloride

N-Ethyldiisopropylamine (0.192 ml) was added to a dichloromethane solution (5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride (219 mg). The mixture was stirred at room temperature for 5 minutes. The reaction mixture was condensed under reduced pressure. Phenylisocyanate (0.065 ml) and toluene (2 ml) were added to the residue. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1→1:0). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (147 mg) as a pale yellow flakes.

1H-NMR (DMSO-d6) δppm: 1.38-1.83 (6H, m), 3.04 (2H, t, J=7.0 Hz), 3.36 (2H, t, J=7.1 Hz), 3.59 (3H, s), 3.65 (2H, t, J=7.1 Hz), 4.03 (2H, t, J=6.4 Hz), 6.60 (1H, d, J=9.5 Hz), 6.93 (1H, t, J=7.3 Hz), 7.18-7.28 (4H, m), 7.38-7.45 (3H, m), 7.81 (1H, d, J=9.5 Hz), 7.89-7.94 (1H, m), 8.26 (1H, s), 8.42 (1H, d, J=8.1 Hz), 8.73 (1H, d, J=5.5 Hz), 8.86 (1H, s)

Example 305 2-Methyl-N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6, 100° C.) δppm: 1.81-2.08 (2H, m), 2.14 (3H, s), 2.40-2.60 (2H, m), 2.70-2.84 (2H, m), 2.85-3.03 (2H, m), 3.21 (3H, s), 3.38-3.73 (4H, m), 3.78-4.00 (2H, m), 6.56-6.82 (2H, m), 6.85-7.04 (2H, m), 7.08-7.31 (3H, m), 7.32-7.48 (1H, m), 7.54-7.84 (1H, m), 8.28-8.60 (2H, m).

Example 306 4-Methyl-N-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-benzamide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6, 100° C.) δppm: 1.86-2.02 (2H, m), 2.32 (3H, s), 2.40-2.60 (2H, m), 2.73-2.88 (2H, m), 2.89-3.02 (2H, m), 3.21 (3H, s), 3.40-3.52 (2H, m), 3.56-3.69 (2H, m), 3.87-3.96 (2H, m), 6.70 (1H, s), 6.62-6.78 (1H, m), 6.93 (1H, d, J=9.0 Hz), 7.10 (2H, d, J=8.0 Hz), 7.17 (2H, d, J=8.0 Hz), 7.41-7.58 (1H, m), 7.73-7.93 (1H, m), 8.38-8.58 (2H, m).

Example 307 N-[3-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-isobutyramide hydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6, 100° C.) δppm: 0.94 (6H, d, J=6.6 Hz), 1.86-2.00 (2H, m), 2.43-2.53 (2H, m), 2.65-2.89 (3H, m), 2.89-3.02 (2H, m), 3.21 (3H, s), 3.34-3.50 (2H, m), 3.52-3.66 (2H, m), 3.90-4.04 (2H, m), 6.70-6.84 (2H, m), 6.89-7.01 (1H, m), 7.56-7.70 (1H, m), 7.98-8.12 (1H, m), 8.50-8.67 (2H, m).

Example 308 N-[3-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yloxy)-propyl]-N-(2-pyridin-3-yl-ethyl)-isonicotinamide dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 45 using appropriate starting materials.

1H-NMR (DMSO-D6, 100° C.) δppm: 1.90-2.05 (2H, m), 2.49-2.53 (2H, m), 2.74-2.88 (2H, m), 2.91-3.12 (2H, m), 3.21 (3H, s), 3.32-3.54 (2H, m), 3.54-3.75 (2H, m), 3.81-4.02 (2H, m), 6.60-6.81 (2H, m), 6.94 (1H, d, J=8.7 Hz), 7.23 (2H, d, J=5.1 Hz), 7.43-7.68 (1H, m), 7.76-8.09 (1H, m), 8.42-8.70 (4H, m).

Examples 310 to 986

The following compounds were obtained in the same manner as in Examples above using appropriate starting materials.

TABLE A

Example No. R1 MS (M + 1) 310 —OCH₃ 492 311 —O(CH₂)₂C₆H₅ 582 312 —N(CH₃)(CH₂)₂N(CH₃)C₆H₅ 624 313 —OCH(C₆H₅)₂ 644 314 —N(CH₃)(CH₂)₂C₆H₅ 595 315 —N(CH₃)(CH₂)₂N(C₂H₅)₂ 590 316 —OC₆H₅ 554 317 —C₆H₅ 538 318 —CH₂CONHC₂H₅ 547

TABLE B

Example MS No. R1 (M + 1) 319

602 320

636 321

569 322

609 323

623 324

637 325

604 326

601 327

542 328

545 329

547 330

586 331

653 332

592 333

587 334

636 335

652 336

609 337

586 338

566 339

581 340

544 341

625 342

596 343

572 344

638 345

637 346

581 347

596 348

600 349

601 350

621 351

585

TABLE C

MS Example No. R1 R2 (M + 1) 352 —(CH₂)₃CH₃ —(CH₂)₃CH₃ 373 353 —CH₂C₆H₅ —(CH₂)₃N(CH₃)₂ 436 354 —CH₃ —(CH₂)₃N(CH₃)CH₂C₆H₅ 436 355 —H —(CH₂)₃N(CH₃)₂ 346 356 —CH₃ —CH₃ 289

TABLE D

Example MS No. R1 R2 (M + 1) 357 —CH₃

357 358 —CH₃

380 359 —C₂H₅

455 360 —CH₃

468 361 —CH₃

399 362 —H

351 363 —H

338 364 —C₂H₅

455 365 —H

383 366 —H

358 367 —CH₃

448 368 —CH₃

496 369 —H

374

TABLE E

Exam- ple MS No. R1 (M + 1) 370

596 371

553 372

635 373

580 374

488 375

530 376

510 377

549 378

516 379

516 380

491 381

554 382

604 383

604 384

495 385

496 386

521 387

523 388

523 389

527 390

597 391

496 392

523 393

496

TABLE F

Example MS No. R1 R2 (M + 1) 394 —(CH₂)₂CH₃ —(CH₂)₃C₆H₅ 554 395 —(CH₂)₂N(CH₃)₂ —CH₂C₆H₅ 555 396 —H —CH₂C(CH₃)₃ 464 397 —CH₃ —(CH₂)₂N(C₂H₅)₂ 507 398 —H —(CH₂)₂SCH₃ 468

TABLE G

Exam- ple MS No. R1 R2 (M + 1) 399 —C₂H₅

572 400 —CH₃

490 401 —H

607 402 —CH₃

518 403 —CH₃

513 404 —CH₃

505 405 —H

504 406 —H

485 407 —H

485 408 —H

485 409 —H

474 410 —CH₃

559 411 —CH₃

533 412 —C₂H₅

556 413 —C₂H₅

518 414 —CH₃

601 415 —H

528 416 —H

462 417 —H

502 418 —H

521 419 —H

562 420 —H

521 421 —CH₂C₆H₅

657 422 —CH₃

591 423 —H

490 424 —H

478 425 —H

499 426 —H

494 427 —H

474 428 —H

491 429 —H

487

TABLE H

Example No. R1 MS (M + 1) 432 —(CH₂)₃CH₃ 519 433 —(CH₂)₂N(CH₃)₂ 534 434 —(CH₂)₃OCH₃ 535 435 —(CH₂)₅CH₃ 547 436 —CO₂C(CH₃)₃ 563

TABLE I

Exam- ple MS No. R1 (M + 1) 437

554 438

554 439

554 440

540 441

541 442

597 443

540 444

659 445

665 446

630 447

579 448

596 449

613 450

579 451

580 452

567 453

553 454

531 455

559 456

560 457

569 458

637 459

604 460

635 461

573 462

649 463

636 464

593 465

623 466

607 467

606 468

596 469

597 470

596 471

611 472

549 473

574 474

543 475

540 476

557 477

554 478

597 479

568 480

622 481

579 482

639 483

597

TABLE J

Example No. R1 MS(M + 1) 484 —CH₂OC₆H₅ 515 485 —(CH₂)₂C₆H₅ 513 486 —CH═CHC₆H₅ 511 487 —(CH₂)₂OC₆H₅ 529 488 —(CH₂)₃C₆H₅ 527 489 —CH(CH₃)₂ 451 490 —(CH₂)₂N(COCH₃)C₆H₅ 570

TABLE K

Example No. R1 MS(M + 1) 491

514 492

486 493

486 494

486 495

500 496

475 497

491 498

475 499

491 500

505 501

505 502

491 503

505 504

596 505

541 506

535 507

535 508

529 509

513 510

529 511

541 512

512 513

512 514

525 515

524 516

524 517

474 518

525 519

513 520

531 521

538 522

538 523

541 524

512 525

554 526

552 527

514 528

491 529

525 530

479 531

493 532

507 533

492 534

503 535

501 536

545 537

527 538

527 539

539 540

543 541

540 542

490 543

492 544

504 545

543 546

556 547

562 548

528 549

543 550

539 551

518 552

476 553

489 554

489 555

489 556

490

TABLE L

Example No. R1 MS(M + 1) 557

472 558

468 559

468 560

470 561

470 562

468 563

467 564

483 565

480 566

508 567

486 568

499 569

499 570

482 571

482 572

484 573

481

TABLE M

Example No. R2 R3 R4 R5 R6 MS(M + 1) 574 —H —H —OCH₃ —H —H 515 575 —H —H —NHCOCH₃ —H —H 542 576 —H —H —H —NHCOCH₃ —H 542 577 —H —H —CF₃ —H —H 553 578 —H —H —H —H —OCH₃ 515 579 —H —H —H —H —CH₃ 499 580 —H —H —H —H —F 503 581 —H —H —H —H —N(CH₃)₂ 528 582 —H —H —H —OCH₃ —H 515 583 —H —H —H —CH₃ —H 499 584 —H —H —COCH₃ —H —H 527 585 —H —H —C₆H₅ —H —H 561 586 —H —H —SO₂NH₂ —H —H 564 587 —H —H

—H —H 550 588 —H —H

—H —H 562

TABLE N

Example No. R2 R3 R4 R5 R6 MS(M + 1) 589 —H —H —H —H —OCH₃ 378 590 —H —H —H —OCH₃ —H 378 591 —H —H —OCH₃ —H —H 378 592 —H —H —H —H —H 348 593 —H —H —H —H —CN 373 594 —H —H —H —CN —H 373 595 —H —H —CN —H —H 373 596 —H —H —H —H —CF₃ 416 597 —H —H —H —CF₃ —H 416 598 —H —H —CF₃ —H —H 416 599 —H —H —H —H —OCF₃ 432 600 —H —H —H —OCF₃ —H 432 601 —H —H —OCF₃ —H —H 432 602 —H —H —H —C₆H₅ —H 424 603 —H —H —H —N(C₂H₅)₂ —H 419 604 —H —H —(CH₂)₂COCH₃ —H —H 418 605 —H —H —COC₂H₅ —H —H 404 606 —H —OH —COCH₃ —H —H 406 607 —H —H —SCH₃ —H —H 394 608 —H —H —C₆H₅ —H —H 424 609 —H —H —H —H —C₆H₅ 424 610 —H —H —H —OC₆H₅ —H 440 611 —H —H —COCH₃ —H —H 390 612 —H —H

—H —H 415 613 —H —H —H —H

415 614 —H —H

—H —H 414 615 —H —H

—H —H 413 616 —H —H

—H —H 556

TABLE O

Example No. R1 MS(M + 1) 617

392 618

398 619

398 620

405 621

419 622

416 623

422 624

399 625

349 626

399 627

349 628

416 629

399 630

413 631

400 632

402 633

363 634

380 635

399 636

402 637

416 638

416 639

430 640

430 641

446 642

445 643

419 644

432 645

435 646

460 647

460 648

460 649

474 650

445 651

431 652

417 653

421 654

431 655

417 656

431 657

445 658

431 659

431 660

405 661

419 662

446 663

432 664

417 665

431 666

403 667

449 668

449 669

435 670

445 671

465

TABLE P

Exam- MS ple No. R1 (M + 1) 672

557 673

545 674

571 675

647 676

555 677

555 678

556 679

578 680

538 681

577 682

530 683

571 684

531 685

571 686

585 687

583 688

575 689

575 690

557 691

556 692

621 693

605

TABLE Q

Example No. R2 R3 R4 R5 R6 MS(M + 1) 694 —H —H —OCH₃ —H —H 532 695 —H —OCH₃ —OCH₃ —H —H 562 696 —Cl —H —H —H —H 536 697 —H —Cl —H —H —H 536 698 —H —H —Cl —H —H 536 699 —H —Cl —Cl —H —H 570 700 —H —H —CH₃ —H —H 516 701 —H —CH₃ —CH₃ —H —H 530 702 —H —H —CO₂C₂H₅ —H —H 574 703 —H —H —CN —H —H 527 704 —H —H —CF₃ —H —H 570 705 —H —H —OCF₃ —H —H 586 706 —H —H —(CH₂)₂CH₃ —H —H 544 707 —H —F —Cl —H —H 554 708 —OCH₃ —H —CH₂CH═CH₂ —H —H 572 709 —H —N(C₂H₅)₂ —H —H —H 573 710 —H —H —CH(CH₃)₂ —H —H 544 711 —H —H —(CH₂)₂COCH₃ —H —H 572 712 —H —NHC₆H₅ —H —H —H 593 713 —H —H —SCH₃ —H —H 548 714

—H —H —H —H 635 715 —H —H —C₆H₅ —H —H 578 716 —H —H —OCH₂C₆H₅ —H —H 608 717 —H —H —CH₂C₆H₅ —H —H 592 718 —H —H —O(CH₂)₇CH₃ —H —H 630 719 —H —OC₆H₅ —H —H —H 594 720 —H —H —(CH₂)₅CH₃ —H —H 586 721 —H —H —NO₂ —H —H 547 722 —H —H —COCH₃ —H —H 544 723 —H —H —H —H —H 502 724 —H —H —NHCOCH₃ —H —H 559 725 —H —H

—H —H 569 726 —H —H

—H —H 568 727 —H —H

—H —H 567 728 —H —H

—H —H 724 729 —H —H

—H —H 584 730 —H —H

—H —H 724 731 —H —H

—H —H 585

TABLE R

Example No. R1 MS(M + 1) 732

546 733

552 734

552 735

559 736

570 737

576 738

553 739

503 740

553 741

503 742

570 743

553 744

543 745

544 746

554 747

542 748

517 749

534 750

553 751

556 752

577 753

584 754

584 755

585 756

599 757

599 758

586 759

614 760

571 761

573 762

575 763

585 764

571 765

585 766

599 767

585 768

587 769

587 770

587 771

601 772

571 773

599 774

599 775

603 776

597

TABLE S

Example No. R1 MS(M + 1) 777 —CH₂C₆H₅ 659 778 —CH₂CH═CH₂ 609 779 —CH₂CH═CHC₆H₅ 685 780 —(CH₂)₃C₆H₅ 687 781 —CH₂COC₆H₅ 687 782 —CH₃ 583 783 —C₂H₅ 597 784 —(CH₂)₂CH₃ 611 785 —CH₂CH(CH₃)₂ 625 786 —(CH₂)₂N(CH₃)₂ 640 787 —(CH₂)₃CH₂CH═CH₂ 651 788 —(CH₂)₃OH 627

TABLE T

Example No. R1 MS(M + 1) 789

693 790

727 791

673 792

735 793

665 794

660 795

660 796

660 797

664

TABLE U

Example No. R1 MS(M + 1) 798

448 799

478 800

455 801

455 802

474 803

405 804

472 805

455 806

469 807

456 808

455 809

483 810

501 811

475 812

488 813

516 814

516 815

487 816

477 817

487 818

487 819

501 820

487 821

489 822

503 823

487 824

461 825

475 826

475 827

489 828

502 829

488 830

473 831

487 832

459 833

505 834

475 835

489 836

501 837

473 838

473 839

474 840

455 841

469 842

443 843

485 844

499 845

487 846

458 847

484 848

455 849

485 850

469 851

473 852

473 853

456 854

461 855

455 856

455 857

455 858

444 859

487 860

473 861

487 862

487 863

487

TABLE V

Example No. R2 R3 R4 R5 R6 MS(M + 1) 864 —H —H —H —H —H 428 865 —H —H —OCH₃ —H —H 458 866 —H —N(CH₃)₂ —H —H —H 471 867 —H —H —N(CH₃)₂ —H —H 471 868 —H —H —CN —H —H 453 869 —COCH₃ —H —H —H —H 470 870 —H —H —COCH₃ —H —H 470 871 —OC₆H₅ —H —H —H —H 520 872 —H —H —OC₆H₅ —H —H 520 873 —CN —H —H —H —H 453 874 —H —H —C₆H₅ —H —H 504 875 —H —H —SO₂CH₃ —H —H 506 876 —H —H —N(C₂H₅)₂ —H —H 499 877 —H —C₆H₅ —H —H —H 504 878 —H —H

—H —H 511 879 —H —H

—H —H 493 880 —H —H

—H —H 494 881 —H

—H —H —H 509 882 —H

—H —H —H 495

TABLE W

Example No. R2 R3 R4 R5 R6 MS(M + 1) 883 —H —H —CH₃ —H —H 456 884 —H —H —F —H —H 460 885 —H —H —OCH₃ —H —H 472 886 —H —H —H —H —CH₃ 456 887 —H —H —H —OCH₃ —H 472 888 —H —H —H —H —OCH₃ 472 889 —H —H —OCH₃ —OH —H 488

TABLE X

Example No. R1 MS(M + 1) 890 —CH₂OC₆H₅ 458 891 —(CH₂)₂C₆H₅ 456 892 —CH═CHC₆H₅ 454 893 —(CH₂)₂OC₆H₅ 472 894 —(CH₂)₃C₆H₅ 470 895 —(CH₂)₄C₆H₅ 484 896 —CH₂SC₆H₅ 474 897 —(CH₂)₂COC₆H₅ 484

TABLE Y

Example No. R1 MS(M + 1) 898

457 899

476 900

488 901

429 902

429 903

429 904

418 905

434 906

418 907

434 908

448 909

448 910

434 911

484 912

484 913

472 914

497 915

514 916

498 917

468 918

455 919

455 920

468 921

475 922

467 923

467 924

469 925

502 926

486 927

481 928

495 929

481 930

500 931

514 932

455 933

527 934

527 935

527 936

539 937

523 938

511 939

495 940

457 941

431 942

444 943

480 944

468 945

436 946

450 947

435 948

446 949

468 950

444 951

486 952

482 953

510 954

433 955

435 956

495 957

447 958

495 959

489 960

517 961

501 962

468 963

513 964

505 965

505 966

505 967

486 968

490 969

419 970

500 971

508 972

508 973

433 974

468 975

484 976

514 977

509 978

482 979

498

TABLE Z Example No . structure MS(M + 1) 981

628 982

446 983

502 984

474 985

530 986

544

Pharmacological Test 1

(1) Production of human Kv1.5-expressing CHO-K1 Cell Lines

CHO-K1 cell lines stably expressing human Kv1.5 channels were prepared in the following manner.

Full-length human Kv1.5 cDNA was cloned from a human heart cDNA library (produced by Stratagene). The obtained human Kv1.5 sequence corresponds to the sequence described in FASEB J. 5, 331-337 (1991).

The obtained human Kv1.5 cDNA was inserted into a plasmid encoding a CMV promoter and a G418 resistance marker to produce a Kv1.5 expression vector. The human Kv1.5 expression vector was transfected into CHO-K1 cells by the lipofectamine method. After culturing the cells in an F-12 medium (produced by Invitrogen Corp.) containing 10% FBS (produced by Invitrogen Corp.) for 3 or 4 days, the medium was replaced with a FBS-containing F-12 medium that included 1,000 μg/ml of G418 (produced by Invitrogen Corp.), and single colonies were isolated. The amount of Kv1.5 channel expression in the single colonies was quantified at the mRNA level by RT-PCR and then quantified at the protein level by western blotting. Finally, the expressed current was analyzed by patch clamp method. Cell lines expressing a current of 200 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamp method.

(2) Production of CHO Cell Line Expressing Human GIRK1/4

CHO cell lines stably expressing human GIRK1/4 channels were prepared in the following manner.

Full-length human GIRK1 cDNA was cloned from HuH cell- and HeLa cell-derived cDNA libraries. Full-length GIRK4 cDNA was amplified from a human heart cDNA library (produced by Clontech Laboratories, Inc.) by PCR using synthetic primers shown in Table 1, and cloned into the Eco-RI restriction enzyme site of pCR-Blunt (produced by Invitrogen Corporation) or into the HincII site of pUC118 (produced by Takara Bio, Inc.).

TABLE 1 Primer Sequence hGIRK1-S 5′-ATGTCTGCACTCCGAAG SEQ ID GAAATTTG-3′ No. 1 hGIRK1-A 5′-TTATGTGAAGCGATCAG SEQ ID AGTTC-3′ No. 2 hGIRK1-F2 5′-GCAGGGTACCCCTTCGT SEQ ID ATTATGTCTGCACTCC-3′ No. 3 hGIRK1-A3 5′-GGTGTCTGCCGAGATTT SEQ ID GA-3′ No. 4 hGIRK1-A4 5′-CCGAGTGTAGGCGATCA SEQ ID CCC-3′ No. 5 hGIRK4-S 5′-ATGGCTGGCGATTCTAG SEQ ID GAATGCC-3′ No. 6 hGIRK4-A 5′-TCTCACCGAGCCCCTGG SEQ ID CCTCCC-3′ No. 7 hGIRK4-S2 5′-AACCAGGACATGGAGAT SEQ ID TGG-3′ No. 8 hGIRK4-A2 5′-GAGAACAGGAAAGCGGA SEQ ID CAC-3′ No. 9

The obtained human GIRK1 and GIRK4 cDNA sequences correspond to known sequences (NCBI database: GIRK1 (NM_(—)002239) and GIRK4 (NM_(—)000890) respectively). The obtained GIRK1 and GIRK4 cDNA sequences were cloned into the Eco-RI restriction enzyme site of pCR-Blunt (available from Invitrogen Corporation) or into the HincII site of pUC118 (available from Takara Bio, Inc.). A GIRK4 expression vector was constructed by insertion into the BamHI-XhoI site of pcDNA5/FRT. A GIRK1 expression vector was constructed by insertion into the KpnI-XhoI site of pcDNA3.1 (+) or pCAG_neo. FLP-IN-CHO cells (produced by Invitrogen Corporation) were transfected with human GIRK1 and GIRK4 expression vectors by using Lipofectamine 2000 (produced by Invitrogen Corporation) according to the protocol enclosed with the reagent or using an electronic induction method (“Nucleofector Kit-T”, produced by Amaxa). First, the cells transfected with the GIRK4 expression vector were cultured in a 10% serum-containing F12 medium (produced by Sigma) supplemented with 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. Then the cells expressing GIRK4 were transfected with the GIRK1 expression vector and were cultured in 10% serum-containing F12 medium supplemented with 350 μg/ml of G418 and 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. to select GIRK1/4 expressing cell lines. Cell populations whose growth was observed after about 2 weeks were isolated using cloning rings, and the obtained single colonies were proliferated. RNA was extracted from single colonies, and single-stranded cDNA was synthesized by a cDNA synthesis kit (produced by Invitrogen Corporation), and the amount of expression was quantified at the mRNA level by real-time PCR (Applied Biosystems, Ltd.). Finally, the expressed current was analyzed by patch clamp method described below. The cell lines expressing a current of 500 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamping method.

(3) Measurement of Ion Channel Current by Patch Clamp Method (Human Kv1.5-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolated table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human Kv1.5-expressing cells were cultured was placed in the perfusion chamber.

Depolarizing stimulation pulses were applied and ionic current was recorded by using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, produced by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, produced by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.

The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

NaCl 140 mM, KCl 40 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES 5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.

The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂ creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(4) Measurement of Ion Channel Current by Patch Clamp Method (Human GIRK1/4-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolation table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human GIRK1/4-expressing cells were cultured was placed in the perfusion chamber.

Hyperpolarizing stimulation pulses were applied and ionic current was recorded using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, manufactured by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, manufactured by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.

The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

NaCl 140 mM, KCl 4 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES 5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.

The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂ creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(5) Measurement of Human Kv1.5 Current

While the membrane potential was holded at −80 mV, depolarizing pulses (−80 mV for 0.05 seconds→□□+40 mV for 0.2 seconds→→□□−40 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure Kv1.5 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and holding the membrane potential at −80 mV, depolarizing pulses were applied. The current obtained during the pulse application was recorded as a current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and holding the membrane potential at −80 mV, depolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration was recorded.

The data was analyzed by using the step end current recorded during the +40 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the +40 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)

(6) Measurement of Human GIRK1/4 Current

While the membrane potential was holded at −80 mV, hyperpolarizing pulses (−80 mV for 0.05 seconds→□□−120 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure GIRK1/4 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. The current obtained during the pulse application was recorded as the current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μM of the test compound. The current obtained using the solution containing the test compound at each concentration were recorded.

The data was analyzed by using the step end current recorded during the −120 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the −120 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)

(7) Calculation of Inhibitory Activity on Kv1.5 Channel Ionic Current and GIRK1/4 Channel Current

The concentration for 50% inhibition of Kv1.5 channel current or GIRK1/4 channel current (IC₅₀ value) was calculated according to the following nonlinear regression equation:

Relative current=1/(1+[Concentration of the compound]/IC₅₀)^(nH)

wherein nH is the Hill coefficient.

Table 2 shows the test results.

TABLE 2 Test Compound KV1.5 IC₅₀ (μM) Compound of Example 14 0.23 Compound of Example 18 0.39 Compound of Example 24 0.32 Compound of Example 26 0.30 Compound of Example 34 0.33 Compound of Example 38 0.38 Compound of Example 40 0.86 Compound of Example 42 0.77 Compound of Example 46 0.42 Compound of Example 62 0.12

3. Third Invention Reference Example 1 Synthesis of ethyl N-(5-methoxy-2-nitrophenyl)-N-methyl malonamate

Sodium hydride (60% in oil, 96 mg) was suspended in 10 ml of dimethylformamide (DMF). N-Methyl-5-methoxy-2-nitroaniline (364 mg) was added thereto at 0° C., and stirring was conducted at room temperature for 30 minutes. Ethyl malonyl chloride (0.38 ml) was added at 0° C. to the stirred mixture, and the reaction mixture was stirred at room temperature overnight. Water was added thereto, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:2). The purified product was concentrated under reduced pressure to give the title compound (554 mg) as a yellow oil.

¹H-NMR (CDCl₃) δppm:

1.24 (3H, t, J=7.1 Hz), 3.15-3.17 (2H, m), 3.25 (3H, s), 3.92 (3H, s), 4.13 (2H, q, J=7.1 Hz), 6.93 (1H, d, J=2.8 Hz), 7.02 (1H, dd, J=2.8 and 9.2 Hz), 8.15 (1H, d, J=9.2 Hz).

Reference Example 2 Synthesis of ethyl N-(2-amino-5-methoxyphenyl)-N-methyl malonamate

Palladium on carbon (10%, 0.5 g) was added to an ethanol solution (150 ml) of ethyl N-(5-methoxy-2-nitrophenyl)-N-methyl malonamate (3.0 g), and catalytic reduction was conducted at room temperature and normal pressure. The reaction mixture was filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give the title compound (2.68 g) as a yellow oil.

¹H-NMR (CDCl₃) δppm:

1.22 (3H, t, J=7.1 Hz), 3.19-3.27 (5H, m), 3.52-3.68 (2H, br), 3.74 (3H, s), 4.11 (2H, q, J=7.1 Hz), 6.62 (1H, d, J=2.7 Hz), 6.73 (1H, d, J=8.7 Hz), 6.79 (1H, dd, J=2.7 and 8.7 Hz).

Reference Example 3 Synthesis of 8-methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium ethoxide (204 mg) was added to an ethanol solution (15 ml) of ethyl N-(2-amino-5-methoxyphenyl)-N-methyl malonamate (266 mg), and stirred at 65° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→10:1). The purified product was concentrated to dryness under reduced pressure to give the title compound (176.3 mg) as a white powder.

¹H-NMR (CDCl₃) δppm:

3.36 (2H, s), 3.43 (3H, s), 3.84 (3H, s), 6.79-6.83 (1H, m), 7.06-7.09 (1H, m), 8.72 (1H, br-s).

Reference Example 4 Synthesis of 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 44 mg) was suspended in dimethylformamide (DMF) (8 ml), and cooled in an ice water bath to 0° C.

8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added to the suspension at the same temperature, and stirred at 0° C. for 1 hour. Ethyl iodide (187 mg) was added to the mixture and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated to dryness under reduced pressure to give the title compound (190.2 mg) as a yellow solid.

¹H-NMR (CDCl₃) δppm:

1.11 (3H, t, J=7.1 Hz), 3.31-3.32 (2H, m), 3.40 (3H, s), 3.59-3.68 (1H, m), 3.85 (3H, s), 4.18-4.30 (1H, m), 6.78 (1H, d, J=2.8 Hz), 6.84 (1H, dd, J=9.0 and 2.8 Hz), 7.26 (1H, d, J=9.0 Hz).

Reference Example 5 Synthesis of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Sodium hydride (60% in oil, 76 mg) was suspended in DMF (8 ml). 1-Ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (190 mg) was added thereto at 0° C., and stirring was conducted at the same temperature for 1 hour. Methyl iodide (0.19 ml) was added to the mixture, and stirred at room temperature for 3 days. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was concentrated to dryness under reduced pressure to give the title compound (169 mg) as a yellow powder.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.65-3.76 (1H, m), 3.85 (3H, s), 4.12-4.24 (1H, m), 6.73 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), 7.22 (1H, d, J=9.0 Hz).

Reference Example 6 Synthesis of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

A 1.0 M boron tribromide/dichloromethane solution (1.22 ml) was added to a dichloromethane solution (3 ml) of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (169 mg) at 0° C., and stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction with the mixture solvent (dichloromethane:methanol=10:1) was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (156.4 mg) as a white powder.

¹H-NMR (CDCl₃) δppm:

0.90 (3H, s), 1.16 (3H, t, J=7.0 Hz), 1.55 (3H, s), 3.41 (3H, s), 3.66-3.78 (1H, m), 4.12-4.23 (1H, m), 6.79 (1H, d, J=2.7 Hz), 6.84 (1H, dd, J=8.8 and 2.7 Hz), 6.88 (1H, d, J=2.7 Hz), 7.18 (1H, d, J=8.8 Hz).

Reference Example 7-Synthesis of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.85 g) and potassium carbonate (1.2 g) were added to 50% water-containing acetonitrile (40 ml), and dissolved by heating to 70° C. 1-Bromo-3-chloropropane (2.1 ml) was added thereto, and heating was conducted under reflux for 6 hours. The reaction mixture was cooled to room temperature. Water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated to dryness under reduced pressure to give the title compound (2.18 g) as a colorless oil.

¹H-NMR (CDCl₃) δppm:

0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.21-2.38 (2H, m), 3.40 (3H, s), 3.63-3.89 (4H, m), 4.10-4.26 (2H, m), 6.74 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=2.8 and 9.0 Hz), 7.21 (1H, d, J=9.0 Hz).

Reference Example 8 Synthesis of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

7-(3-Chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (2.18 g) and sodium iodide (4.8 g) were added to acetone (50 ml), and heated under reflux for 8.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure to give the title compound (2.76 g) as a colorless oil.

¹H-NMR (CDCl₃) δppm:

0.87 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.26-2.34 (2H, m), 3.39 (2H, t, J=6.6 Hz), 3.65-3.76 (1H, m), 3.41 (3H, s), 4.07 (2H, t, J=5.8 Hz), 4.12-4.24 (1H, m), 6.74 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0 and 2.8 Hz), 7.22 (1H, d, J=9.0 Hz).

Reference Example 9 Synthesis of 3-iodoquinolin-4-ol

Potassium carbonate (5.2 g) was added to a DMF solution (50 ml) of 4-hydroxy quinoline (5.0 g) and the mixture was stirred. Iodine (9.6 g) was added to the mixture, followed by stirring at room temperature for 3 hours. A saturated sodium hydrogencarbonate aqueous solution (73 ml) of 25% sodium sulfite, and water (50 ml) were added to the reaction mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was washed with water and dried to give the title compound (9.0 g) as a white powder.

mp: 288 to 294° C. (dec.)

Reference Example 10 Synthesis of 3-bromoquinolin-4-ol

N-Bromosuccinimide (1.3 g) was added to a DMF solution (15 ml) of 4-hydroxy quinoline (1.0 g) and the mixture was stirred at room temperature for 15 hours. A sodium hydrogencarbonate aqueous solution of 25% sodium sulfite was added to the mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was dissolved in a mixture of ethyl acetate and methanol, and an insoluble matter was removed by filtration. The filtrate was condensed under reduced pressure, and the residue was washed with ethyl acetate and dried to give the title compound (1.1 g) as a white powder.

mp: 286 to 287° C.

Reference Example 11 Synthesis of 3-bromo-1H-quinolin-2-one

Hydrogen peroxide solution (5.9 ml) was added to a THF solution (16 ml) of methyltrioxorhenium (VII) (24 mg). The mixture was stirred for 10 minutes at room temperature. 3-Bromoquinoline (4.0 g) was added thereto, and the mixture was stirred at room temperature for four days. Ethyl acetate (20 ml) was added to the reaction mixture. 20% Sodium sulfite aqueous solution (30 ml) was added slowly to the mixture under ice cooling. The mixture was stirred at room temperature. The organic layer was condensed to a half volume under reduced pressure. Ethyl acetate (20 ml) and 15% potassium carbonate aqueous solution (19 ml) were added thereto, and the organic layer was extracted. 15% Potassium carbonate aqueous solution (19 ml) of p-toluenesulfonyl chloride (4 g) were added thereto. The mixture was stirred for 10 minutes at room temperature. The generated insoluble matter was separated, washed with ethyl acetate, water, and then with ether, and dried to give the title compound (3.2 g) as a white powder.

mp: 263 to 265° C.

Reference Example 12 Synthesis of 1-(pyridin-3-yl)-2,3-dihydrobenzoimidazol-2-one

N,N′-Carbonyldiimidazole (0.57 g) was added to a DMF solution (5 ml) of N-pyridine-3-ylbenzene-1,2-diamine (0.5 g). The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.5 g) as a pale whitish purple powder.

mp: 232 to 233° C. (dec.).

Reference Example 13 Synthesis of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one

Sodium hydride (60% in oil, 0.32 g) was suspended in DMF (10 ml), and was cooled to 0° C. in an ice water bath. 2-Methyl-5H-furo[3,2-c]pyridin-4-one (0.57 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde dimethylacetal (2.3 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochrolic acid (2 ml) was added to an acetone solution (10 ml) of the residue, and the liquid was stirred at 70° C. for 10 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.56 g) as a white solid.

¹H-NMR (DMSO-D₆), δppm: 2.36 (s, 3H), 3.86 (d, J=5.4 Hz, 2H), 4.94-4.98 (m, 1H), 6.04 (d, J=6.4 Hz, 2H), 6.52 (s, 1H), 6.59 (d, J=7.4 Hz, 1H), 7.41 (d, J=7.4 H, 1H).

Reference Example 14 Synthesis of 5-(1H-benzoimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one

5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (2.1 g) and o-phenylenediamine (1.1 g) were suspended in ethanol (20 ml) Sodium hydrogensulfite (5.2 g) was added, and the mixture was heated and stirred overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound (2.25 g).

¹H NMR (CDCl₃), δppm: 2.36 (3H, s), 5.44 (2H, s), 6.55 (1H, s), 6.73 (1H, d, J=7.4 Hz), 7.05-7.15 (2H, m), 7.43 (1H, d, J=7.0 Hz), 7.50 (1H, d, J=8.3 Hz), 7.70 (1H, d, J=7.4 Hz).

Reference Example 15 Synthesis of 3-(pyridin-3-yl)-1H-quinolin-4-one

2N Hydrochloric acid (10 ml) was added to a DMF solution (5 ml) of 4-chloro-(3-pyridin-3-yl)quinoline (0.51 g), and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, 2N sodium hydroxide aqueous solution (10 ml) was added dropwise under ice cooling. The mixture was stirred. The precipitated insoluble matter was separated, washed with water and ether, and dried to give the title compound (0.35 g) as a pale whitish purple powder.

mp: 240 to 242° C. (dec.)

Reference Example 16 Synthesis of 5-[{1-(3-chloropropyl)-1H-benzoimidazol-2-yl}methyl]-2-methyl-5H-furo[3,2-c]pyridin-4-one

5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.75 g), 1-bromo-3-chloropropane (1.3 ml), and potassium carbonate (0.95 g) were added to 50% hydrous acetonitrile (16 ml). The mixture was heated overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.18 g) as a colorless oily matter.

¹H NMR (CDCl₃), δppm: 2.02-2.09 (2H, m), 2.41 (3H, s), 3.54 (2H, t, J=6.1 Hz), 4.55-4.61 (2H, m), 5.56 (2H, s), 6.51-6.53 (2H, m), 7.24-7.32 (2H, m), 7.40-7.46 (1H, m), 7.54 (1H, d, J=5.9 Hz), 7.73-7.79 (1H, m).

Reference Example 17 Synthesis of 5-(3-chloropropyl)-2-methyl-5H-furo[3,2-c]pyridin-4-one

Methane sulfonyl chloride (0.24 ml) was added to a dichloromethane solution (10 ml) of 5-(3-hydroxypropyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and triethylamine (0.45 ml). The mixture was stirred at room temperature for two days. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.16 g) as a white amorphous solid.

¹H NMR (CDCl₃), δppm: 2.25-2.41 (2H, m), 2.41 (3H, s), 3.56 (2H, t, J=6.1 Hz), 4.18 (2H, t, 6.6 Hz), 6.48 (1H, d, J=7.4 Hz), 6.55 (1H, s), 7.17 (1H, d, J=7.4 Hz).

Reference Example 18 Synthesis of 7-(2-chloroethoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.2 g) and potassium carbonate (0.95 g) were added to 50% hydrous acetonitrile (24 ml). The mixture was heated to 70° C. to be dissolved. 1-Bromo-2-chloroethane (1.9 ml) was added, and the mixture was heated under reflux for 7 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (1.4 g) as a colorless oily matter.

¹H NMR (CDCl₃), δppm: 0.86 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 3.40 (3H, s), 3.64-3.77 (1H, m), 3.85 (2H, t, J=5.7 Hz), 4.03-4.15 (1H, m), 4.26 (2H, t, J=5.7 Hz), 6.77 (1H, d, J=2.8 Hz), 6.83 (1H, dd, J=9.0, 2.8 Hz), 7.23 (1H, d, J=9.0 Hz).

Reference Example 19 Synthesis of 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

10% Palladium on carbon (0.7 g) was added to a methanol solution (30 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(3-nitropyridin-4-ylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.8 g). The mixture was subjected to catalytic reduction at room temperature under normal pressure. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure to give the title compound (1.4 g) as an orange amorphous solid.

¹H NMR (CDCl₃), δppm: 0.86 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.12-2.24 (2H, m), 3.40 (3H, m), 3.40-3.52 (2H, m), 3.63-3.74 (1H, m), 4.03-4.14 (3H, m), 6.51 (1H, d, J=5.4 Hz), 6.75-6.76 (1H, m), 6.84 (1H, dd, J=9.0, 2.8 Hz), 7.22 (1H, d, J=9.0 Hz), 7.93 (1H, s), 7.98 (1H, d, J=5.4 Hz).

Example 1 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-phenylpiperidin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride

Potassium carbonate (0.54 g), sodium iodide (0.21 g), and 2-phenyl piperidine (0.23 g) were added to a DMF solution (15 ml) of 7-(3-chloropropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.44 g). The mixture was stirred at 70° C. for 5 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was washed with water and then with saturated saline, and dried with anhydrous magnesium sulfate. After condensation under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1). The purified product was condensed under reduced pressure. A 4N-Hydrogen chloride ethyl acetate solution (0.2 ml) was added to an ethyl acetate solution (10 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound (0.18 g) as a white amorphous solid.

¹H NMR (CDCl₃), δppm: 0.82 (3H, s), 1.12 (3H, t, J=7.0 Hz), 1.51 (3H, s), 1.89-3.22 (11H, m), 3.36 (3H, s), 3.62-3.97 (5H, m), 4.09-4.18 (1H, m), 6.53-6.54 (1H, m), 6.62-6.67 (1H, m), 7.16 (1H, d, J=9.0 Hz), 7.36-7.47 (3H, m), 7.61-7.90 (2H, m), 12.40 (1H, brs).

Example 2 Synthesis of 7-[3-((R)-2,4-dibenzylpiperazin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

The synthesis of the title compound was performed in the same manner as in Example 1 using appropriate starting materials.

¹H NMR (DMSO-d₆), δppm: 0.75 (3H, s), 1.01 (3H, t, J=6.8 Hz), 1.33 (3H, s), 2.15-2.40 (2H, m), 2.83-3.90 (13H, m), 3.97-4.61 (7H, m), 6.96-7.01 (2H, m), 7.28-7.44 (9H, m), 7.59 (2H, br).

Example 3 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{3-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-ylmethyl)benzimidazol-1-yl]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and potassium carbonate (0.9 g) were added to a DMF solution (2 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.43 g). The mixture was stirred at 60° C. overnight. After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.43 g) as a white amorphous solid.

¹H NMR (CDCl₃), δppm: 0.85 (3H, s), 1.15 (3H, t, J=7.1 Hz), 1.53 (3H, s), 2.12-2.23 (2H, m), 2.40 (3H, s), 3.38 (3H, s), 3.61-3.72 (1H, m), 3.95 (2H, t, J=5.7 Hz), 4.05-4.15 (1H, m), 4.65 (2H, t, J=6.5 Hz), 5.53 (2H, s), 6.49-6.55 (2H, m), 6.70-6.71 (1H, m), 6.74-6.80 (1H, m), 7.19 (1H, d, J=9.0 Hz), 7.24-7.27 (2H, m), 7.33-7.38 (1H, m), 7.54 (1H, d, J=7.5 Hz), 7.75-7.79 (1H, m).

Example 4 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{2-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-ylmethyl)benzimidazol-1-yl]ethoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Potassium carbonate (0.58 g), sodium iodide (0.21 g), and 5-(1H-benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.39 g) were added to a DMF solution (30 ml) of 7-(2-chloroethoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.47 g). The mixture was stirred at 65° C. overnight. The mixture was further stirred at 100° C. overnight. After the reaction mixture was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5→85:15). The purified product was condensed to dryness under reduced pressure to give the title compound (0.44 g) as a white amorphous solid.

¹H NMR (CDCl₃), δppm: 0.77 (3H, s), 1.09 (3H, t, J=7.1 Hz), 1.49 (3H, s), 2.40 (3H, s), 3.26 (3H, s), 3.61-3.74 (1H, m), 4.05-4.18 (1H, m), 4.24 (2H, t, J=5.0 Hz), 4.93 (2H, t, J=5.0 Hz), 5.55-5.66 (2H, m), 6.44-6.45 (1H, m), 6.51-6.54 (2H, m), 6.57-6.64 (1H, m), 7.00 (1H, d, J=9.0 Hz), 7.25-7.36 (2H, m), 7.58-7.62 (1H, m), 7.63 (1H, d, 7.6 Hz), 7.77-7.80 (1H, m).

Example 5 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-phenyl-benzoimidazol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride

2-Phenyl-1H-benzimidazole (0.2 g) and potassium carbonate (0.29 g) were added to a DMF solution (5 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.49 g). The mixture was stirred at 60° C. for 7 hours. The reaction mixture was poured to ice water (50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution (1.0 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (0.32 g) as a white powder.

mp: 132 to 134° C.

Example 6 Synthesis of 7-[3-(4-chloro-2-oxo-3-phenyl-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

4-Chloro-3-phenyl-1H-quinoline-2-one (0.3 g) was suspended in DMF (6 ml). Sodium hydride (60% in oil)(51 mg) was added, and the mixture was stirred for 15 minutes at room temperature. 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.55 g) was added thereto and the mixture was stirred at room temperature for 7 days. The reaction mixture was poured to ice water (50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:3). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether, thereby obtaining the title compound (0.28 g) as a white powder.

mp: 122 to 128° C.

Example 7 Synthesis of 1-ethyl-3,3,5-trimethyl-7-{3-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-ylmethyl)imidazo[4,5-c]pyridin-1-yl]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione dihydrochloride

A DMF solution (4 ml) of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.20 g), 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.37 g), and sodium hydrogensulfite (0.47 g) were heated at 180° C. for 10 minutes (microwave reactor). After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5→60:40). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration, and dried to give the title compound (0.47 g) as a white amorphous solid.

¹H NMR (DMSO-d₆), δppm: 0.70 (3H, s), 0.95 (3H, t, J=7.1 Hz), 1.30 (3H, s), 2.31-2.41 (2H, m), 2.40 (3H, s), 3.29 (3H, s), 3.60-3.70 (1H, m), 3.98-4.09 (1H, m), 4.16 (2H, t, J=6.0 Hz), 4.79 (2H, t, J=6.6 Hz), 5.67 (2H, s), 6.54 (1H, s), 6.80-6.85 (3H, m), 7.33 (1H, d, J=6.5 Hz), 7.76 (1H, d, J=7.5 Hz), 8.33 (1H, d, J=6.5 Hz), 8.60 (1H, d, J=6.5 Hz), 9.36 (1H, s).

Example 8 Synthesis of 7-[3-(3-bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

Under ice cooling, sodium hydride (60% in oil, 0.2 g) was added to a DMF solution (10 ml) of 3-bromo-1H-quinoline-2-one (1.0 g). The mixture was stirred at the same temperature for 15 minutes. Lithium bromide (0.76 g) was added to the mixture, and the liquid was stirred at the same temperature for another 15 minutes, and then at room temperature for an hour. The reaction mixture was cooled to 0° C., and 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.1 g) was added thereto. The mixture was stirred at room temperature for 2 hours, and at 50° C. for 8 hours. The reaction mixture was poured to ice water, and the generated insoluble matter was separated. The insoluble matter was dissolved in a mixed solvent of ethyl acetate and dichloromethane. The liquid was dried with sodium sulfate and condensed under reduced pressure. Ethyl acetate was added to the residue. The generated insoluble matter was separated and dried to give the title compound (1.2 g) as a white powder.

mp: 168 to 169° C.

Example 9 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-2H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.

White powder

mp: 134 to 135° C.

Example 10 Synthesis of 1-ethyl-7-[3-(3-iodo-4-oxo-4H-quinolin-1-yl)propoxy]-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.

White powder

mp: 97 to 106° C.

Example 11 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(4-oxo-3-(pyridin-3-yl)-4H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.

White powder

mp: 199 to 201° C.

Example 12 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(4-oxo-4H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.

White powder

mp: 174 to 177° C.

Example 13 Synthesis of 7-[3-(3-bromo-4-oxo-4H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 8 using appropriate starting materials.

White powder

mp: 180 to 183° C.

Example 14 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-phenyl-2,3-dihydrobenzimidazol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.

¹H NMR (CDCl₃), δppm: 0.84 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.27-2.41 (2H, m), 3.36 (3H, s), 3.6-3.78 (1H, m), 4.09 (2H, t, J=5.9 Hz), 4.11-4.26 (1H, m), 4.20 (2H, t, J=6.6 Hz), 6.68 (1H, d, J=2.8 Hz), 6.80 (1H, dd, J=2.8, 9.0 Hz), 6.99-7.14 (4H, m), 7.19 (1H, d, J=9.0 Hz), 7.33-7.47 (1H, m), 7.47-7.58 (4H, m).

Example 15 Synthesis of 1-ethyl-7-[3-(3-hydroxy-2-oxo-3-phenyl-2,3-dihydroindol-1-yl)prop oxy]-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.

White powder

mp: 153 to 156° C.

Example 16 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-(pyridin-3-yl)-2,3-dihydrobenzimidazol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hydrochloride

1-(Pyridin-3-yl)-1,3-dihydrobenzimidazole-2-one (0.2 g) was suspended in DMF (6 ml). Sodium hydride (55% in oil, 48 mg) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes.

1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.45 g) was added to the mixture. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to ice water (100 ml), followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 0.5N-hydrogen chloride ethanol solution (1.9 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound (0.38 g) as a white powder.

White powder

mp: 119 to 125° C.

Example 17 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2′-oxospiro[[1,3]dioxolane-2,3′-indoline]-1′-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.

White powder

mp: 143 to 147° C.

Example 18 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-phenylindol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.

White powder

mp: 140 to 142° C.

Example 19 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-phenyl-2H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

7-[3-(3-Bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), phenylboronic acid (0.12 g), tetrakis (triphenyl phosphine) palladium (0) (0.11 g), and potassium carbonate (0.39 g) were added to dioxane (5 ml). The mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→3:1). The purified product was condensed to dryness under reduced pressure, thereby obtaining the title compound (0.34 g) as a white amorphous solid.

¹H NMR (CDCl₃), δppm: 0.84 (3H, s), 1.14 (3H, t, J=7.1 Hz), 1.52 (3H, s), 2.27-2.42 (2H, m), 3.37 (3H, s), 3.62-3.80 (1H, m), 4.05-4.28 (3H, m), 4.62 (2H, t, J=7.2 Hz), 6.72 (1H, d, J=2.7 Hz), 6.83 (1H, dd, J=2.7, 9.0 Hz), 7.19 (1H, d, J=9.0 Hz), 7.20-7.30 (1H, m), 7.32-7.58 (5H, m), 7.60-7.67 (1H, m), 7.67-7.74 (2H, m), 7.84 (1H, s).

Example 20 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(4-oxo-3-phenyl-4H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.

White powder

mp: 150 to 152° C.

Example 21 Synthesis of 1-ethyl-7-{3-[3-(6-methoxypyridin-3-yl)-4-oxo-4H-quinolin-1-yl]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 19 using appropriate starting materials.

White powder

mp: 159 to 161° C.

Example 22 Synthesis of 1-ethyl-7-{3-[3-(6-methoxypyridin-3-yl)-4-oxo-4H-quinoline-1-yl]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione mesylate

Methanesulfonic acid (0.024 ml) was added to an ethyl acetate/isopropyl alcohol solution (1:1, 8 ml) of 1-ethyl-7-{3-[3-(6-methoxypyridin-3-yl)-4-oxo-4H-quinoline-1-yl]propoxy}-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.2 g) at 0° C., which was stirred at the same temperature for 2 hours. The precipitated insoluble matter was separated, washed with isopropyl alcohol, and dried to give the title compound (0.19 g) as a white powder.

White powder

mp: 188 to 189° C.

Example 23 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-3-phenyl-3,4-dihydro-2H-quinolin-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

10% Palladium on carbon (20 mg) was added to an ethanol/ethyl acetate solution (1:1, 4 ml) of 7-[3-(4-chloro-2-oxo-3-phenyl-2H-quinoline-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.19 g). The mixture was subjected to catalytic reduction at 50° C. under normal pressure for 6 hours. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound (0.1 g) as a white powder.

mp: 100 to 105° C.

Example 24 Synthesis of 7-[3-(2,3-dioxo-2,3-dihydroindol-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.

Orange powder

mp: 162 to 163° C.

Example 25 Synthesis of 1-ethyl-3,3,5-trimethyl-7-[3-(2-oxo-2,3-dihydroindol-1-yl)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione

7-[3-(2,3-Dioxo-2,3-dihydroindol-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.3 g) was suspended in hydrazine hydrate (3 ml), and the liquid was stirred for two hours while heated under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=85:15). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound (0.18 g) as a pale brownish white powder.

mp: 146 to 149° C.

Example 26 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(3-((3-(1-oxoisoquinolin-2(2H)-yl)propyl)(pyridin-4-ylmethyl)amino)propoxy)-1H-benzo[b][1,4]diazepine-2,4 (3H,5H)-dione

The synthesis of the title compound was performed in the same manner as in Example 6 using appropriate starting materials.

¹H-NMR (CDCl₃) δppm: 0.84 (s, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.51 (s, 3H), 1.90-2.00 (m, 4H), 2.58 (t, J=6.8 Hz, 2H), 2.68 (t, J=6.8 Hz, 2H), 3.38 (s, 3H), 3.61 (s, 2H), 3.62-3.72 (m, 1H), 3.95-4.00 (m, 4H), 4.08-4.22 (m, 1H), 6.44 (d, J=7.3 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 6.75 (dd, J=9.0 and 2.7 Hz, 1H), 6.95 (d, J=7.3 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.25-7.27 (m, 2H), 7.45-7.52 (m, 2H), 7.60-7.70 (m, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.48 (d, J=1.5 Hz, 2H).

Example 27 Synthesis of 1-ethyl-3,3,5-trimethyl-7-(3-((3-(1-oxoisoquinolin-2(2H)-yl)propyl)(pyridin-4-ylmethyl)amino)propoxy)-1H-benzo[b][1,4]diazepine-2,4 (3H,5H)-dione dihydrochloride

A 4N-hydrogen chloride in ethyl acetate solution (0.3 ml) was added to an ethyl acetate solution (3 ml) of 1-ethyl-3,3,5-trimethyl-7-(3-((3-(1-oxoisoquinolin-2(2H)-yl)propy 1) (pyridin-4-ylmethyl)amino)propoxy)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (159 mg), and the mixture was stirred at room temperature for two hours. The reaction mixture was condensed under reduced pressure to give the title compound (178 mg) as a amorphous solid.

¹H-NMR (DMSO-d₆) δppm: 0.74 (s, 3H), 1.00 (t, J=7.0 Hz, 3H), 1.32 (s, 3H), 2.25 (br, 4H), 3.01-3.31 (m, 4H), 3.31 (s, 3H), 3.61-3.70 (m, 1H), 4.00-4.12 (m, 5H), 4.61 (br, 2H), 6.65 (d, J=7.4 Hz, 1H), 6.86-6.91 (m, 2H), 7.39 (d, J=8.9 Hz, 1H), 7.47-7.53 (m, 2H), 7.65-7.74 (m, 2H), 8.08 (br, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.80 (br, 2H).

Pharmacological Test 1 (1) Production of Human Kv1.5-Expressing CHO-K1 Cell Lines

CHO-K1 cell lines stably expressing human Kv1.5 channels were prepared in the following manner.

Full-length human Kv1.5 cDNA was cloned from a human heart cDNA library (produced by Stratagene). The obtained human Kv1.5 sequence corresponds to the sequence described in FASEB J. 5, 331-337 (1991).

The obtained human Kv1.5 cDNA was inserted into a plasmid encoding a CMV promoter and a G418 resistance marker to produce a Kv1.5 expression vector. The human Kv1.5 expression vector was transfected into CHO-K1 cells by the lipofectamine method. After culturing the cells in an F-12 medium (produced by Invitrogen Corp.) containing 10% FBS (produced by Invitrogen Corp.) for 3 or 4 days, the medium was replaced with a FBS-containing F-12 medium that included 1,000 μg/ml of G418 (produced by Invitrogen Corp.), and single colonies were isolated. The amount of Kv1.5 channel expression in the single colonies was quantified at the mRNA level by RT-PCR and then quantified at the protein level by western blotting. Finally, the expressed current was analyzed by patch clamp method. Cell lines expressing a current of 200 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamp method.

(2) Production of CHO Cell Line Expressing Human GIRK1/4

CHO cell lines stably expressing human GIRK1/4 channels were prepared in the following manner.

Full-length human GIRK1 cDNA was cloned from HuH cell- and HeLa cell-derived cDNA libraries. Full-length GIRK4 cDNA was amplified from a human heart cDNA library (produced by Clontech Laboratories, Inc.) by PCR using synthetic primers shown in Table 1, and cloned into the Eco-RI restriction enzyme site of pCR-Blunt (produced by Invitrogen Corporation) or into the HincII site of pUC118 (produced by Takara Bio, Inc.).

TABLE 1 Primer Sequence hGIRK1-S 5′-ATGTCTGCACTCCGAAG SEQ ID GAAATTTG-3′ No. 1 hGIRK1-A 5′-TTATGTGAAGCGATCAG SEQ ID AGTTC-3′ No. 2 hGIRK1-F2 5′-GCAGGGTACCCCTTCGT SEQ ID ATTATGTCTGCACTCC-3′ No. 3 hGIRK1-A3 5′-GGTGTCTGCCGAGATTT SEQ ID GA-3′ No. 4 hGIRK1-A4 5′-CCGAGTGTAGGCGATCA SEQ ID CCC-3′ No. 5 hGIRK4-S 5′-ATGGCTGGCGATTCTAG SEQ ID GAATGCC-3′ No. 6 hGIRK4-A 5′-TCTCACCGAGCCCCTGG SEQ ID CCTCCC-3′ No. 7 hGIRK4-S2 5′-AACCAGGACATGGAGAT SEQ ID TGG-3′ No. 8 hGIRK4-A2 5′-GAGAACAGGAAAGCGGA SEQ ID CAC-3′ No. 9

The obtained human GIRK1 and GIRK4 cDNA sequences correspond to known sequences (NCBI database: GIRK1 (NM_(—)002239) and GIRK4 (NM_(—)000890) respectively). The obtained GIRK1 and GIRK4 cDNA sequences were cloned into the Eco-RI restriction enzyme site of pCR-Blunt (available from Invitrogen Corporation) or into the HincII site of pUC118 (available from Takara Bio, Inc.). A GIRK4 expression vector was constructed by insertion into the BamHI-XhoI site of pcDNA5/FRT. A GIRK1 expression vector was constructed by insertion into the KpnI-XhoI site of pcDNA3.1 (+) or pCAG_neo. FLP-IN-CHO cells (produced by Invitrogen Corporation) were transfected with human GIRK1 and GIRK4 expression vectors by using Lipofectamine 2000 (produced by Invitrogen Corporation) according to the protocol enclosed with the reagent or using an electronic induction method (“Nucleofector Kit-T”, produced by Amaxa). First, the cells transfected with the GIRK4 expression vector were cultured in a 10% serum-containing F12 medium (produced by Sigma) supplemented with 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. Then the cells expressing GIRK4 were transfected with the GIRK1 expression vector and were cultured in 10% serum-containing F12 medium supplemented with 350 μg/ml of G418 and 600 μg/ml of hygromycin in an incubator with 5% carbon dioxide at 37° C. to select GIRK1/4 expressing cell lines. Cell populations whose growth was observed after about 2 weeks were isolated using cloning rings, and the obtained single colonies were proliferated. RNA was extracted from single colonies, and single-stranded cDNA was synthesized by a cDNA synthesis kit (produced by Invitrogen Corporation), and the amount of expression was quantified at the mRNA level by real-time PCR (Applied Biosystems, Ltd.). Finally, the expressed current was analyzed by patch clamp method described below. The cell lines expressing a current of 500 pA or more per cell were selected as channel-expressing cell lines for activity measurement by patch clamping method.

(3) Measurement of Ion Channel Current by Patch Clamp Method (Human Kv1.5-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolated table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human Kv1.5-expressing cells were cultured was placed in the perfusion chamber.

Depolarizing stimulation pulses were applied and ionic current was recorded by using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, produced by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, produced by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.

The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

NaCl 140 mM, KCl 40 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES 5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.

The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂ creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(4) Measurement of Ion Channel Current by Patch Clamp Method (Human GIRK1/4-Expressing CHO-K1 Cell Line)

An experiment was carried out using a patch clamp setup at room temperature (20 to 26° C.). A perfusion chamber having a diameter of 20 mm (flow rate: about 5 ml/min) was mounted on the stage of a phase-contrast inverted microscope (produced by Nikon Corporation) placed on a vibration isolation table. A poly-L-lysine (produced by Sigma)-coated coverslip (diameter: 15 mm, produced by Matsunami Glass Ind., Ltd.) on which human GIRK1/4-expressing cells were cultured was placed in the perfusion chamber.

Hyperpolarizing stimulation pulses were applied and ionic current was recorded using a patch clamp amplifier (EPC-7 or EPC-7 PLUS, manufactured by HEKA) and a personal computer (manufactured by IBM Corp.) in which software for data acquisition and analysis of ion channel current (PULSE 8.77, manufactured by HEKA) was installed. The current was measured in the whole-cell configuration of the patch-clamp technique. The tip (resistance: 2 to 4 MΩ) of a borosilicate glass pipette (produced by Sutter Instrument Co.) was gently placed on the cell membrane by using a three-dimensional mechanical micromanipulator (produced by Shoshin EM Corporation). Weak suction resulted in giga seal formation (the pipette resistance increased to more than 1 GΩ). Subsequently, stronger suction was applied to break the cell membrane. The capacitative current derived from the cell membrane was corrected using a patch clamp amplifier. Subsequently, the series resistance (Rs) between the pipette and the interior of the cell was measured and corrected.

The composition of the extracellular solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

NaCl 140 mM, KCl 4 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, NaH₂PO₄ 0.33 mM, HEPES 5 mM Glucose 5.5 mM (pH = 7.4)

Each test compound was prepared as a 1000-fold concentrated stock solution that was dissolved in DMSO and then diluted in the extracellular solution.

The composition of the electrode internal solution used is shown below. Unless otherwise specified, these components were obtained from Wako Pure Chemical Industries, Ltd.

KOH 100 mM, KCl 40 mM, Aspartic acid 70 mM, MgCl₂ 1 mM, MgATP 5 mM, K₂ creatine phosphate 5 mM, HEPES 5 mM EGTA 5 mM (pH = 7.2)

(5) Measurement of Human Kv1.5 Current

While the membrane potential was holded at −80 mV, depolarizing pulses (−80 mV for 0.05 seconds→□□+40 mV for 0.2 seconds→□□−40 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure Kv1.5 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and holding the membrane potential at −80 mV, depolarizing pulses were applied. The current obtained during the pulse application was recorded as a current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μm of a test compound and holding the membrane potential at −80 mV, depolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μm of the test compound and then using an extracellular solution containing 10 μm of the test compound. The current obtained using the solution containing the test compound at each concentration was recorded.

The data was analyzed by using the step end current recorded during the +40 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the +40 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)

(6) Measurement of Human GIRK1/4 Current

While the membrane potential was holded at −80 mV, hyperpolarizing pulses (−80 mV for 0.05 seconds→□□−120 mV for 0.2 seconds→□□−80 mV for 0.05 seconds) were applied at a stimulation frequency of 1 Hz to measure GIRK1/4 channel current. More specifically, first, while perfusing an extracellular solution containing 0.1% DMSO and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. The current obtained during the pulse application was recorded as the current in the absence of the test compounds. Subsequently, while perfusing an extracellular solution containing 0.1 μM of a test compound and maintaining the membrane potential at −80 mV, hyperpolarizing pulses were applied. After the inhibitory effect of the test compound had been stabilized, the current was recorded. The same procedure was repeated using an extracellular solution containing 1 μM of the test compound and then using an extracellular solution containing 10 μm of the test compound. The current obtained using the solution containing the test compound at each concentration were recorded.

The data was analyzed by using the step end current recorded during the −120 mV depolarizing stimulation. The “step end current” refers to the average current flowing for a period of 195 to 199 milliseconds from the start of the −120 mV depolarizing pulse stimulation.

Using the step end current in the presence of the test compound and the step end current in the absence of the test compound, the relative current in the solution containing the test compound at each concentration was calculated according to the following formula:

Relative current=(Step end current in the presence of the test compound)/(Step end current in the absence of the test compound)

(7) Calculation of Inhibitory Activity on Kv1.5 Channel Ionic Current and GIRK1/4 Channel Current

The concentration for 50% inhibition of Kv1.5 channel current or GIRK1/4 channel current (IC₅₀ value) was calculated according to the following nonlinear regression equation:

Relative current=1/(1+[Concentration of the compound]/IC₅₀)^(nH)

wherein nH is the Hill coefficient.

Table 2 shows the test results.

TABLE 2 Test Compound KV1.5 IC₅₀ (μM) Compound of Example 2 1.10 Compound of Example 5 0.87 Compound of Example 6 0.60 Compound of Example 14 0.40 Compound of Example 20 0.34 Compound of Example 21 0.84 Compound of Example 22 1.50 

1. An amino compound represented by General Formula (1):

or a salt thereof, wherein R¹ and R² are each independently hydrogen or organic group; X_(A) and X_(B) are each independently a bond, alkylene, alkenylene, —CO—, —SO₂—, or —CONH—, wherein each of the alkylene and alkenylene chains can optionally contain one or more substituents selected from the group consisting of —S—, —C(═S)—, —SO₂—, —CO—, —O—, —NH—, —CONH— and —SO₂NH—, and the hydrogen atom (H) bonded to the nitrogen atom (N) in X_(A) and X_(B) is optionally substituted with a substituent selected from the group consisting of lower alkyl, phenyl lower alkyl and phenyl; A¹ is lower alkylene optionally substituted with one or more substituents selected from the group consisting of hydroxyl and oxo; R³ is (i) a heterocyclic group which is optionally substituted with one or more substituents, or (ii) an aryl group substituted with one or more substituents selected from the group consisting of oxo, lower alkyl, carboxyl, halo-lower alkyl, lower alkanoyl lower alkyl, phenyl lower alkyl, cyclo lower alkyl, lower alkoxy, halo lower alkoxy, phenyl lower alkoxy, phenoxy, cyano, hydroxyl, halogen, nitro, lower alkyl thio, lower alkanoyl, lower alkoxy carbonyl, lower alkenyl, phenyl, triazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzo[d]oxazolyl, benzo[d]thiazolyl and the group represented by General Formula (2):

wherein Y is a bond, lower alkylene, or —CO—; R⁴ and R⁵ are each independently hydrogen, lower alkyl, cyclo lower alkyl, phenyl, or lower alkanoyl; or R⁴ and R⁵ may be linked to form a ring together with the neighboring nitrogen, and the ring may optionally have one or more substituents. 